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					       ANTINEOPLASTIC DRUGS

Neoplasm

   The medical term for "Cancer" or "tumor" is neoplasm, which means "a relatively
autonomous growth of tissue". Tumor is a general term indicating any abnormal mass or
growth of tissue, not necessarily life-threatening. A "cancerous tumor" is a malignant
neoplasm with potential danger.
The critical difference between benign and malignant neoplasms is that benign tumors do
not metastasize, whereas malignant tumors (or cancer)do. A metastasis is a secondary
growth originating from the primary tumor growing elsewhere in the body.

In the other words:
Cancer is a disease characterized by malignant cells which proliferate in an uncontrolled
manner, invade adjacent tissues and organs forming daughter colonies.

Chemotherapeutic agents:

    Antineoplastic drugs (anticancer) are agents which are employed to suppress the growth
and extension of neoplasm.
Except for the hormones they are all cytotoxic, non has a specifity for cancerous tissues.
They appear to interfere with functions concern with cell division, so that the proliferative
tissues including neoplasms are the most affected. It follows that the major undesirable side
effects (expect for hormones) are extended upon highly proliferative normal tissues such as
the bone marrow, lymph tissue and gastro-intestinal mucosa.

Antineoplastic drugs may be classified into:

I- Alkylating agents

a) Nitrogen mustard
b) Aziridines (ethylenimines)
c) Sulphonic acid esters
d) Nitrosourea
e) Miscellaneous alkylating agent.

II- Antimetabolite:

       Antagonists of metabolites involved in nucleic acid          synthesis:-
 a) Folic acid antagonists
 b) Pyrimidine antagonists
 c) Purine antagonists

III- Antibiotics
IV - Plant products
V - Hormones.
VI - Immunotherapy.




   At present there is no known chemical compounds which will cure any form of cancer.
Therapy is still limited largely to surgery and treatment with ionizing radiation. There are
many anticancer agents which are able to produce relief of pain and temporary
disappearance of tumors.
The effective dose is often very close to the toxic dose.

                                       I. Alkylating agents

Mode of action

   Alkylating agents are chemically reactive compounds capable of alkylating certain
functional groups in biological centers. The functional groups concerned include amino
groups, thiolate anions of proteins, ring nitrogen atoms and phosphate anion of nucleotides.

         The majority of alkylating agents act by routes involving a first or a second
nucleophilic substitution reaction mechanism. Alkylation, specially with sulphur and
nitrogen mustard, takes place through neighboring group participation of RS and R2N which
results in an internal displacement reaction and formation of solvent stabilized strained, and
highly reactive three membered ring. The reaction rates of alkylating agents and reactivities
of the competing nucleophiles were found to be dependent on the pH and concentration of
the reactants. So, a medium which enhances ionization of thiols and carboxylic acids will be
much favorable to generate reactive nucleophiles than another in which ionization does not
occur. In addition, amine in the free state are more active as nucleophiles than when existing
in the protonated form.

        The polyfunctional alkylating agents have both cytotoxic and a mutagenic action.
They also inhibit glycolysis, respiration, protein and nucleic acid synthesis, as well as a
number of membrane function. The bifunctional alkylating agents are much active as
cytotoxic agents than the monofunctional ones. Their effect in cytotoxicity has been
attributed to their ability to cross-link twin strand with DNA.

         Some clinically important alkylating agents are not active until they have been
transformed by metabolic processes. The leading example of this group is
cyclophosphamide, which is converted by hepatic cytochrome P - 450 into the
corresponding 4-hydroxy derivative by way of the 4-hydroperoxy intermediate. The 4-
hydroxy derivative is a carbinolamine in equilibrium with the open-chain aminoaldehyde
form. Nonenzymatic decomposition of the latter form generates phosphoramide mustard and
acrolein the conjugate base of phosphoramide mustard cyclizes to the aziridinium ion, which
is the principal cross-linking alkylator formed from cyclophosphamide.
a. Nitrogen mustard

    Nitrogen mustard are chracaterized by having in common a nitrogen atom to which is
attached one 2-chloroethyl group for monofunctional(R- = H); or two 2-chloroethyl groups
for bifunctional compounds (R- = CH2 CH2 Cl) as shown in the general formula (1):
            CH2 CH2 Cl
         R-N
            R-

   In the body, at physiological pH, nitrogen mustard undergo an easy unimolecular
conversion into the relatively stable ethylenimmonium ion (aziridinium ion 2). This intern
reacts bimolecularly with any available nucleophilic centers and regains
the straight chain structure (3):
(Chart I)

   CH2 CH2 Cl slow            Y-     CH2 CH2 Y
 R-N      ------> R-N      ------> R-N
   CH2 CH2 Cl         CH2 CH2 Cl       CH2 CH2 Cl
                  (2)           (3)

   The same reaction can take place with the second 2-chloroethyl group and due to this
property, the nitrogen mustard is called a bifunctional nitrogen mustard (Chart II):

   CH2 CH2 Y slow    CH2 CH2 Y Z-     CH2 CH2 Y
 R-N     ------> R-N     -----> R-N
   CH2 CH2Cl                   CH2 CH2 Z

 Y, Z = Nucleophile

    The chemotherapeutic effects of nitrogen mustard show great variation depending on the
nature of R,. Thus, when R is an aliphatic group, the compound is more soluble in lipids and
hence is highly active. When R is an aromatic moiety, both chemical and biological activity
will be dependent on how much basicity of the nitrogen will be strengthened or reduced by
substituents in the phenyl group. So, an electron donating substituents increase reactivity of
the mustard function, whereas electron withdrawing substituents decrease it. In general, the
more the unshared pair electron is localized on the nitrogen, the higher will be the activity of
the aromatic nitrogen mustard and vice-versa. Furthermore, the replacement of chlorine in
the ethyl chain by other halogens was found to induce a great effect on the chemical as well
as on the biological activity of nitrogen mustard. For example, the antitumor activity of P-
[bis (2-bromoethyl)amino]-benzenethiol (4) was reported as being superior to that of the
moderately active chloroanalog. The monofunctional N4 (2-bromoethyl)-N4-ethyl
sulphanilamide (5b) was even more potent than the bifunctional compound (5a).



        CH2 CH2 Br               CH2 CH2 Br
 HS       N        H2NSO2      N
          CH2 CH2 Br           CH2 CH2 X

    (4)               (5) a: X = Br
                         b: X = H

   The mixed bromochloro mustard (6) has also been prepared and its activity as compared
with the dibromo and dichloro analog, was decreased.

         The flouro nitrogen mustard proved to be the least reactive halogen derivatives due
to the slower rate of aziridinium ion formation than in case of the chloro nitrogen mustard.

   As representative examples, the following is a brief presentation of some active
anticancer compounds to show the effect of structural variations on the anticancer activity.
Methyl bis (2-chloroethyl) amine (7) is the simplest, active and most widely known
prototype aliphatic nitrogen mustard. The aromatic nitrogen mustard: chlorambucil is very
potent against walker carcinosarcoma 256.


   CH3O             CH2 CH2 Br        CH2 CH2Cl
            CH2 N          CH3 N
   CH3O             CH2 CH2 Cl        CH2 CH2 Cl

            (6)             (7)


   The compounds contained the nitrogen mustard function either introduced in various
position of amino-acid molecule or made up through replacement of the amino-hydrogen of
the acid by 2- chloroethyl group showed that the nitrogen mustard derived from L-amino
acids were more active than those obtained from the D-isomers and the activity of the
racemic mixture was mainly due to the presence of L-isomer in the mixture e.g. melphalan.

        The nitrogen mustard derived from phenylalanine and the nitrogen mustard (8-a) and
(8-b), derived from the lower amino-acid glycine and alanine, respectively, are examples of
the compounds which showed strong activity.

   On the other hand , various nuclei were used as carriers for nitrogen mustard function to
direct the compounds to specific target centers e.g. mannitol mustard: Degranol (9) which is
an effective anticancer agent, containing carbohydrate moiety as a carrier.




   ClCH2 CH2 R             CH2 NHCH2 CH2 Cl
         N-CHCOOH      HO-C-H
   ClCH2 CH2         HO-C-H
                 H-C-OH
     (8)          H-C-OH
      a: R = H       CH2 NHCH2 CH2Cl
      b: R = CH3
                   (9)

   Nitrogen mustard containing vitamin B6; pyridoxine (10), Chloroquine (11), quinacrine
(12), purine (13), (14) and benzimidazole (15), i.e. containing heterocyclic ring as carrier
have also been synthesized and found to be effective in inhibition of some animal tumor and
leukemia. When the nitrogen mustard function was attached to the purine ring via thioether
linkage, as in 6 {bis [2-chloroethyl] amino ethylthio} purine dihydrochloride (16), a high
activity against a wide spectrum of animal tumor, was observed.

                          CH3        CH2 ch2 Cl

           CH2 CH2 Cl            NHCH (CH2)3 - N
  HO      CH2 N                        CH2 CH2 Cl
           CH2 CH2 Cl               2HCl

  CH3

        (10)              (11)

          CH3         CH2 CH2 Cl

         NHCH-(CH2)3-N
               CH2 CH2Cl

               (12)


      NHCH2 CH2 N(CH2 CH2 Cl)2


                            -N(CH2 CH2 Cl)2

                                   HCl
        (13)                (14)


                       SCH2 CH2N (CH2 CH2 Cl)2


        CH2 N(CH2 CH2 Cl)2
          HCl
          (15)                   (16)
       Synthesis of nitrogen mustard generally follows one of the following scheme:-
               CH2 CH2 OH               CH2 CH2 Cl
                        SOCl2
1) RNH2 + 2 -----> RN             ------> RN
               CH2 CH2 OH               CH2 CH2Cl
    CH2 CH2 OH            CH2 CH2 OH
                              | SOCl2
2) HN      + RCl ------> RN             ----+

   CH2 CH2 OH              CH2 CH2 OH

If R = CH3 , Mustine HCl, N-methyl,N,N-bis (2-chloroethyl)amine HCl, is produced.

 Assay:

1- Hydrolysis of mustine HCl by hot alcoholic potassium hydroxide     converts the all
chlorine atoms into chloride ions (3 ions)    which are then determined by Vo1hard's
method.

2- U.S.P. Method:
   Mustine HCl is assayed by treating the drug with sodium                 bicarbonate,adding
known excess of standard sodium               thiosulfate,leave for 2-5 hours, then titrate with
standard    iodine using starch as indicator.


    CH2 CH2-Cl    H2O     +
  CH3-N        ----> CH3-N      Na2 S2 O3
    CH2 CH2-Cl          CH2 CH2 Cl ---------->

                      +                                                   CH2 CH2 S2 O3Na
H2 O     CH2CH2S2O3Na
  CH3 N         ---------> CH3 -N
     CH2 CH2-Cl     Na2S2O3       CH2CH2S2O3Na

Uses of mustine:

   It is a cytotoxic agent used specially in the treatment of certain Leukemia and in
carcinoma of the breast and lungs.

N.B:

   The monofunctional 2-chloroethyl-N,N-dimethyl-amine (CH3)2N-CH2CH2Cl was
inactive replacement of methyl group with other groups which alter basicity affects both
chemical and biological activity.




                                                MUSTRONE

  Methchlorethamine N-oxide, Nitromin, HN2 oxide
N,N-bis (B-chloroethyl) N-methylamine, N-oxide.

    O CH2 CH2 Cl
  CH3 - N
        CH2 CH2 Cl

        Conversion of the nitrogen to its oxide, reduces greatly its toxicity with small
reduction in its antitumor activity. Its activity is most likely due to the formation of the
highly reactive cyclic oximonium ions which has the ability of alkylate as nitrogen mustard.

Uses:

       Mustrone is used for the treatment acute, chronic leukemia
and breast cancer.


                                          CHLORAMBUCIL

(Leukeran)R (ClCH2 CH2 )2 N-         CH2 CH2 CH2 COOH

     4- {P- [bis(2-chloroethyl) amino] phenyl} butyric acid

       It ia an example of nitrogen mustard containing an aromatic ring. It can be
synthesized from 4-phenylbutyric acid.

            1)Nitration              CH3
    - CH2CH2CH2 COOH -------------->O2N- -(CH2)3 COOCH
            2)Isopropyl/HCl             CH3

                             1)Red.H2/pd                                        2)Ethylene
oxide
    HOCH2 CH2                       CH3                             N-    -(CH2)3 COOCH
|
    HOCH2 CH2                  CH3 ---------+
    1) POCl3
    --------------> Chlorambucil
    2) Hydrolysis


Assay:

   A weighed quantity is hydrolysed by alcoholic sodium hydroxide and chloride ions
determined by volhard method.




Uses:

   Similar to mustine HCl. It is active orally. It is the agent of choice in the treatment of
chronic lymphocytic leukemia and the agent of second choice in the treatment of
choriocarcinoma, testicular carcinoma in combination with methotrexate.

                                       MELPHALAN HCl

AlkeranR ClCH2CH2
          N- - CH2CH-COOH
     ClCH2CH2      NH2

    4-Bis-(2-Chloroethyl)-amino-L-phenylalanine

Preparation:- as under Chlorambucil starting from phenylalanine.

  Melphalan is a derivative of phenylalanine containing a nitrogen mustard side-chain.
The L-isomer melphalan has been used in the treatment of a wide variety of tumors.

Assay:

   By volhard's methods as usual.


                        CYCLOPHOSPHAMIDE


(cytoxan)R (ClCH2CH2)2N-P=O           .H2O


 2- [Bis (2-Chloroethyl)            amino]   tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide
monohydrate.
Preparation:

   ClCH2CH2             ClCH2CH2 Cl
        NH + POCl3 ------>    N-P=O
   ClCH2CH2        -HCl ClCH2CH2 Cl

 Bis(2-Chloroethyl) amino        N,N-bis (2-Chloroethyl)
                       Phosphamide dichloride
  3-aminopropanol
--------------------> Cyclophosphamide

Properties:

    It is white powder, soluble in water, its aqueous solution slowly liberates chloride ion due
to the formation of ethylenimonium ion.



Assay

    Cyclophosphamide is assayed for phosphorous
a) By fusion with oxidizing fusion mixture (K2CO3 & KNO3) the              produced phosphate
is determined gravimetrically.

b) Volumetric method:
  By prolonged heating with a mixture of con. H2So4 and HNO3 to          convert phosphorous
to orthophosphoric acid then treated                   with molybdic acid & the resulting
phosphomolybdic acid was              precipitated by slow addition of quinoline,the washed
precipitate is dissolved in excess N/2 NaOH & back titrate the excess with N/2 HCl using
a mixture of ph.ph. & thymol blue        solution as indicator. The quinoline is too weak as a
base to interfere with titration.

Mode of action:

    Cyclophosphamide is inactive in vitro. In vivo the activity is due to the cleavage of the
cyclic P-N bond or P-O bond followed by cleavage of the phosphamide bridge connecting
the mustard nitrogen and the former phosphatide bridge. This cleavage are produced by
cellular phosphatase which occurs in greater amount in cancerous tissues and cleavage does
not occur in circulating plasma since phosphatase (phosphamidase) occur in great amount in
cancerous cells, the drug have a more selective action than other cytotoxic agents being
stable in the gastrointestinal tract it may be given orally.

                                       URACIL MUSTARD

    (ClCH2CH2)2N-         5- bis (2-chloroethyl) aminouracil
   The structure of uracil mustard combines the features of a nitrogen mustard and
nucleotide antimetabolite .


                                       b- Aziridines

                (Ethylenimines)

   This type of compounds, is transferred in a slightly acidic medium to an active alkylating
intermediate .
e.g.



   These compounds can be given orally & absorbed in the active form. They are
inactivated by the gastric juice and should be given on an empty stomach with NaHCO3.




                                       Trimethylene melamine

                         Treatmine TEM

                         2,4,6 - Tris (1-aziridinyl)-triazine

Preparations:

    NH2 NH2 NH3
   O=C  C=O ------->      -------->          +3HN
    N N            <-------
      C

  Cyanouric acid

    Cold aq. NaOH
  -------------------> TEM + 3 H2O


   The ethylenimine (aziridine) is conveniently prepared by heating the acid sulphate ester
of ethanolamine with sodium hydroxide.
             NaOH
   H2NCH2CH2OSO3H ----------> NH + NaHSO4
                                                  THIOTEPA

         Tris (1-aziridinyl) phosphine sulphide
                  S

               N P N

                 N

Preparation:

   Thiotepa can be made by condensation of aziridine with thiophosphoryl chloride in
benzene solution, using triethylamine as condensing agent.
                   TEA
       3 NH + SPCl3 ----------> Thiotepa + 3HCl

Assay:

    A weighed sample is treated with excess sodium thiosulfate solution, which results in
fission of the ethylenimino rings and formation of three moles of sodium hydroxide for each
mole of thiotepa. This alkali titrated with N/10 HCl pH4 using methyl orange as indicator.

   N- + Na2S2O3 +H2O -------> -HN-CH2CH2-S-SO2Na + NaOH



Uses:

       Thiotepa is of value in the treatment of certain carcinoma, especially metastatic
carcinoma of the breast or ovary.

                                       C-Sulfonic Acid Esters
Busulfan:

       Tetramethylene dimethanosulphonate, (Myleran)R
   CH3 SO2 O (CH2)4 OSO2 CH3

Preparation:

        It may be prepared by esterifying 1,4-butanediol with       methanesulfonyl
chloride in the presence of pyridine

   HO(CH2)4OH + 2CH3 .SO2 Cl-------> Busulfan

Assay:
       A weighed quantity is hydrolyzed by refluxing with water, methansulfonic acid is
produced which can be titrated with standard alkali using ph.ph. as indicator.

    2CH3 SO3H + 2NaOH ph.ph.> 2CH3SO3Na + 2H2O

Mode of action:

   Busulfan is an alkylating undergoes a process known as "sulfur stripping" in which its
interaction with thiol compounds such as glutathione or cysteine results in loss of two
equivalent of methanesulfonic acid and formation of cyclic sulfonium intermediate which
readily converted into the metabolite 3- hydroxy thiolane-1,1-dioxide.
Busulfan is useful in the treatment of chronic granulocytic
leukemia.

CH2CH2OSO2CH3              CH2CH2 +
       + HS - R --->       S-R + 2CH3SO-3 + H+
CH2CH2OSO2CH3              CH2CH2


                  CH2CH2 O
                     S
                  CH2CH2 O
                                     D- Nitrosourea

   A somewhat different type of alkylating agent is the N-alkyl-N-nitrosourea. Compounds
of this class are unstable in aqueous solution under physiologic conditions. They produce
carbonium ions (also called carbenium ions) that can alkylate, and isocyanates that can
carbamoylate for example.


            ClCH2CH2N-C-NH-R
               N=O

  ClCH2CH2N = N-OH          +      O=C=N-R

   ClCH2CH2+ + N2 + OH-           Carbamoylation

  Alkylation

Decomposition of chlorethylnitrosourea form chlorethyl carbonium ion and a
carbamoylating isocyanate group.

       H
CARMUSTINE.            NCH2CH2Cl
     O=C
            NCH2CH2Cl
            N=O

    1,3-Bis (2-chloroethyl)-1-nitrosourea; BCNU; -
This compound was synthesized by treating 1,3-bis(2-chloroethyl) urea with sodium nitrite
and formic acid.

    Because of its ability to cross the blood-brain barrier carmustine is used against brain
tumors and other tumors, such as leukemia,that have metastasized to the brain. It is used
also as secondary therapy in combination with other agents for Hodgkin's disease and other
lymphoma:

Carmustine is given as a single dose by intravenous injection

Lomustine: NH
    O=C
       NCH2CH2Cl
       N=O

       1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea.

        The compound was synthesized using procedure involved treating
cyclohexylisocyanate with 2-aminoethanol then POCl3, followed by nitrosation of the
resulting intermediate,
1-(2-chloroethyl)-3- cyclohexylurea.

   Lomustine is used against both primary and metastatic brain tumors and as secondary
therapy in Hodgkin's disease. The most common adverse reaction are nausea and vomiting,
thrombocytopenia, and leukopenia. As with carmustine, the myelo suppression caused by
lomustine is delayed.
The recommended dosage of lomustine is 130-mg/m2 orally.

       H2NCH2CH2OH       HN 1)POCl3
     N=CO ------------> C=O -------------> LOMUSTINE
               HOCH2CH2 2)NaNO2/HCOOH



E- Miscellaneous Alkylating Agents:

pipobroman
       O   O
   BrCH2CH2C-N N-CCH2CH2Br

       1,4- Bis (3-bromopropionyl) piperazine; Vercyte
Preparation:

        Piperazine, in dry chloroform solution, is doubly condensed with 3-bromopropionyl
chloride using an excess of piperazine to encourage the dehydrochlorination.

                                       II.ANTIMETABOLITES

   An antimetabolite is defined as a compound so similar in chemical structure to an
essential metabolite that it can replace the metabolite in biologic systems. It is, however,
unable to support the growth of cell as the metabolite can. The result is malfunction of the
normal metabolism of cells.

Antagonists of Metabolites Involved in the synthesis of Nucleic Acids

a) Antimetabolite of Folic Acid.

         Folic acid (Pteroylglutamic acid)

       A large number of structural modifications of pteroylglutamic acid have been
synthesized and, in general, the variations fall into the following classes:

1) Changes in the substituents in the 2-and 4-positions.
2) Replacement of the pteridin by other cyclic systems.
3) Alteration of the 9,10 configuration.
4) Replacement of glutamic acid by other amino acids
5) Replacement of p-aminobenzoic acid by position isomers and by        sulfanilic acid.
6) Substitution in the benzene ring of the p-aminobenzoic acid.

        Many of these analogs competitively inhibit the activity of pteroylglutamic acid,
folic acid, folinic acid and others, both in microorganisms and in animals. Some of these
analogs have been used in studies involving leukemia and neoplasms, both in experimental
animals and in man.

                                         Methotrexate
   10
4-AMINO-N-methylpteroylglutamic acid

         CH2-N-     CONHCH(CH2)2COOH
          CH3       COOH


Methotrexate inhibit the enzyme dihydrofolic acid reductase.

Assay:

Spectrophotometry:
       Methotrexate is the drug of choice for the treatment of acute leukemia in children.

               AMINOPTERIN SODIUM

  Sodium -4-aminofolate
H2N-

        CH2NH-        CONHCHCH2 CH2 COONa
                    COONa
    H2N

            b.Pyrimidine Antagonists

 Fluorouracil; 5- Fluorouracil

             O
           HN       F

           O    N
               H


        Fluorouracil, with the small structural change from uracil, was found to possess
substantial antitumor activity. There is evidence to indicate that the drug acts by blocking
the methylation reaction of deoxyuridylic acid to thymidylic acid and in this way, interferes
with the synthesis of deoxyribonucleic acid.
                               O
                            HN      R

                            O N
                     O
Deoxyuridylic Acid R = H         HO-P-O-CH2
Thymidylic Acid R = CH3          HO


                C- Purine Antagonists
                 1) Mercaptopurine

                       SH
6- Mercaptopurine, Purinethol     N       N

                        N    N
                            H
        It is the 6-thiol analog of adenine. Mercaptopurine is an antimetabolite for adenine in
the synthesis of nucleotide by living cells. Therefore, it can repress cell division and at least
cause temporary remission of leukemia and chronic myelogenous leukemia.

Preparation:

  OH
 N
    NaNO2                   Red        HO
 N   ------->             --------->   + CH ----->
    HOAc                    H/Ni        O

Assay:

         1) Kjeldahl nitrogen estimation.
         2) Non-aqueous titration.

                      2- Thioguanine

       Thioguanine is a close relative of mercaptopurine and, like mercaptopurine, It is an
antimetabolite which interferes with purine metabolism. It is indicated for the treatment of
leukemia.
Thioguanine is 2-aminopurine-6-thiol


         SH       H

     N            N

   N2N        N       N

PREPARATION:

    OH            SH H
      H        N    N
  N    N P2S5
       ------>    N N
H2N N N          H2N


                                                 III. Antibiotics


  Some antibiotics show potential anticancer activity, are, e.g., Actinomycin D;
Dactinomycin (Cosmegen)R and Daunorubicin
Dactinomycin is an isoactinomycin; have two identical pentapeptide lactones on the 3-
phenoxazone-1,9-dicarboxylic acid, with an amino acid sequence of L-threonine, D-valine,
L-proline, sarcosine, and L-N-methylvaline.




Mode of action:

        Intercalate into double helical DNA which changes its physical properties e.g. length
and viscosity.
The main biochemical consequence of the intercalation is the inhibition of DNA and RNA
synthesis.

        Anthracyclines are glycosides of anthracyclinones, a glycone containing
anthraquinone chromophore within a linear hydrocarbon skeleton related to that of the
tetracycline.

      Daunorubicin is a glycoside formed between daunomycinone and L-daunosamine,
whereas doxorubicin is its 14-hydroxy analog.

                                              e. Plant Products

1. Colchicine and Podophyllotoxin

    Colchicine I an alkaloid isolated from the plant colchicum autumanle, inhibit cellular
mitosis in metaphase . One of the colchicine analogies, demecolcine II, is somewhat
effective
    in chronic myelocytic leukemia, butts antileukemic effects are observed only at toxic or
near toxic doses.
Podophyllotoxin lignin isolated from the plant podophyllum peltatum, resembles colchicine
in its effects on mitosis. It has no real clinical utility.

Vinca alkaloids are the most important antineoplastic agents , cause mitotic arrest by
promoting the dissolution of microtubule in cells in the cytoplasm.
Vinblastine is the most active compound isolated from vinca rosa.




                       f. Hormones

   Cancer of certain organs or cells that are normally subjects to hormonal regulation may
respond favorably to hormonal therapy.
The first effective chemotherapy of human cancer with structurally defined entities was the
treatment of cancer of the breast and of the prostate with hormonal agents. Hormonal
therapy is based on the concept that neoplastic cells derived from a hormone-responsive
organ may likewise be subjects to hormonal control, at least during some part of the life of
the neoplasm.

Androgens

    Testosterone has beneficial effects in certain types of advanced breast cancer. It is
usually employed as its propionate ester. However, it causes high incidence of
masculinizing effects
which severely limit its usefulness. Other androgens used in the treatment of breast cancer
include dihydrotestosteron, D-homo-testosterone propionate and others, all elicited
responses similar to that of testosterone propionate. It has been suggested that the androgens
increase muscle tone by stimulating protein synthesis, and thereby cause a sense of well-
being which may be of psychological value in cancer therapy.

Estrogens:

   Many estrogenic compounds with antiandrogenic activity are employed in the treatment
of prostatic cancer, e.g., synthetic estrogen, estradiol, chlormadinone acetate and
cyproterone acetate. The latter two compounds have the advantage of being nonfeminizing
and are most active antiandrogens known at the present time.

Corticosteroid

   Adrenocortical steroids constitute one of several classes of agents useful in the therapy of
leukemia and lymphomas.
Because the corticosteroid act rapidly, they are especially useful for rapid induction of
remission in acute leukemia. ACTH and cortisone were first reported to produce temporary
remissions of acute and chronic leukemia and beneficial effects in lymphomas. Althoufg the
natural corticosteroids cortisone and hydrocortisone produce remissions of leukemia, they
also cause undesirableside effects owing to disturbances of electrolyte balance. The
synthetic glucocorticoids prednisone, prednisolone, triamcinolone, dexamethasone and
fluorometholone are all effective in inducing remissions in acute leukemia, with less
pronounced side effects.


              VI Immunotherapy

        Stimulations of the body's immune system provide avaluable methed of tumor
treament. The development of tumors implies that the immune surveillance system is not
functioning properly, this indicated by the high rate of cancer in organ-transplant patients
whose immune systems are supressed by drugs, and a high correlation between cancer and
immune deficiency disease such as bactrial and viral infections.
        levamisole, an anthelmintic agent found to be an immunostimulant, it acts by
stimulating the responsiveness of lymphocytes to tumor antigens.
Tilorone is a synthetic compound that show immunostimulant activity. It stimulate the
production of interferon. Its antitumor action appears to be an effect on "T" cells originating
in the thymus.




                                      Drug Metabolism



    Humans are exposed throughout their lifetime to a large variety of drugs
and nonessential foreign compounds e.g. exposure to vapors of volatile
chemical, smoking or ingestion of toxins and pesticides in vegetables.
Drugs and foreign compounds collectivity referred as (xenobiotics).

    Most of xenobiotics undergo enzymatic biotransformations in liver and
extrahepatic tissues are eliminated by excretion as inactive hydrophilic
metabolites (the process is referred as detoxication) or detoxification.

    In some cases, especially during oxidative metabolism, numerous
chemical procarcinogens form reactive metabolites capable of binding
covalently to nucleic acid a critical step to carcinogenicity.       Therefore,
biotransformation study of xenobiotics becomes a prerequisite for the
assessment of drug safety.

    The metabolic process which lead to the formation of metabolites having
therapeutic or toxic effects is referred as bioactivation.

General Pathways of Drug Metabolism :

I- Drug Biotransformation Pathway ((Phase I) (Functionalization
   reaction) : Which include :

    1- Oxidative biotransformation.

    2- Reductive biotransformation.

    3- Hydrolytic biotransformation.

    The purpose is to introduce a polar function group e.g., OH, COOH,
NH2, SH into the molecule make it more polar water soluble products and
more readily excreted or suitable to conjugation with phase II.

II- Drug conjugation pathways (phase II)
    Enzymatic synthesis whereby a small polar and ionizable endogenous
compound attached to the function group, e.g.: acetyl, sulphate, glucuronic
acid, glycine and other amino acids. Where, the conjugated metabolites are
readly excreted in the urine and devoid activity and toxicity.

Role of cyp 450 in oxidation reaction

RH + NADPH + O2 + H+  ROH + NADP+ + H2O
RH (xenobiotics)
ROH (Oxidised metabolites)
   NADPH (reduced form of nicotinamide adenosine dinucleotide
phosphate).

  It should be emphasized that during this oxidative process, one atom of
molecular (O2) is introduced into the substrate RH to form ROH, while the
other oxygen incorborated into water.

  The enzyme system carrying out this biotransformation are referred to as
mixed function oxidase or monooxygenases, which is actually made up of
cyp 450, which is responsible for transferring an oxygen atom to the
substrate, NADPH dependent cyp 450 reductase and NADH. The latter two
supply electron needed in the overall metabolic oxidation.

Sites of drugs biotransformation

  The liver is the most important organ in drug metabolism, it is rich in
almost all the drug metabolizing enzyme.

  Orally administered drugs that are absorbed through GIT must first pass
through the liver (first pass metabolism). Therefore, they are susceptible to
hepatic metabolism prior to reaching the systemic circulation and as a result
decrease oral bioavailability. Other tissues such as kidney, lungs, adrenal
glands, placenta, brain, skin and GIT have some degree of drug metabolizing
capacity.

I- Functionalization reaction (Phase I)

  1- Oxidative reaction

   The liver microsomal enzyme cytochrome p-450 (a heme protein) is a
mixed    function    oxidaze     system       responsible   for   most   oxidative
biotransformation.

The ability of cyp 450 to form a biologically inactive ferrous carbonyl
complex with carbon monoxide CO with its major absorption band at 450
nm led to its discovery and name.

Also (FMO) falvine monooxygenase is liver microsomol monooxygenase
enzyme responsible for S, N hetero atom oxidation.

a- Oxidation of aromatic moiety (Hydroxylation)
    Almost all aromatic hydroxylation are proceed initially through epoxide
intermediate which rearranges rapidly to the hydroxy product.

                       R                  R                 R




                                              O
                                                            OH
                    Arene         Arenepoxide          Arenol

e.g.:
                               NHCOCH3            NHCOCH3




                                                  OH
                        Drug              Metabolite
                      Acetanilide        Acetaminophen
                             CH3                                                CH3
        O CH2      CH CH2NH C H                            O CH2      CH CH2NH C H
                   OH        CH3                                      OH        CH3




                                                           OH
  Drug                                           Metabolite
 Propranolol                                   Hydroxy derivative
-blocker                               (hydroxylation in p-position)
                              CH3                         CH3
                     H2C CH         NH2            H2C CH       NH2




                                                     OH
                  Drug                         Metabolite
              Amphetamine
        indirect adrenergic agent




N.B. Hydroxylation occur in the more electron rich ring e.g.:

               Bu         O                          Bu         O

                          N                                     N
               O     N                              O      N




                                                          OH
                   Drug                          Metabolite
          Phenylbutazone                   oxyphenylbutazone

b- Oxidation of benzylic carbon (methyl oxidation)
    Carbon atom attached to aromatic ring (benzylic) are susceptible to
oxidation forming the corresponding primary alcohol metabolite which
oxidized further to aldehyde and carboxylic acid.

e.g. : Oral hypoglycemic tolbutamide.

            O
   SO2NH C NHC4H9                R                   R




   CH3                           CH2OH               COOH

Tolbutamide                 Alc. Metabolite    Carboxylic acid metabolite

c- Oxidation of olefins
    The metabolic oxidation of olefinic C=C lead to the corresponding
epoxide which tend to be somewhat more stable. The epoxide formed is
minor product owing to their further conversion to the corresponding 1,2-
diols.

e.g. :.
                 Cl                                      Cl
                                              O
H2C CHCH2O                  CH2COOH        H2C CHCH2O           CH2COOH


             Alcofenac                     Alcophenic epoxide (minor)
          (anti-inflammatory)
                       Cl
            OH OH
          H2C CHCH2O             CH2COOH


   Dihydroxy alcofenac (major urinary metabolite)
                                   O                        HO         OH

       N

   O
           NH2

Carbmazepine               10,H-epoxide             Trans-10,11-dihydroxy-
anticonvulsant                                      carbmazepine

d- Oxidation at allylic carbon :
   Microsomal hydroxylation at allylic carbon is commonly observed in
drug metabolism. e.g. : Hexobarbital, sedative and hypnotic.

   The 3-hydroxylated metabolite is susceptible to glucuronoid conjuga-
tion as well as further oxidation to the 3`-oxo-compound.




             O                                  O                                 O
    H3C              CH3               H3C              CH3                 H3C           CH3
                 N                                  N                                 N

       O     N       O                  O       N       O                    O    N       O
             H                HO                H                      O          H
 Hexobarbital                3`-Hydroxyhexobarbital                    3`-Oxohexobarbital

                                                        O
                                             H3C                 CH3
                                                            N

                                               O        N        O

                                        O             H
                                             glucuronide



e- Oxidation at carbon  to carbonyl and imines :
            CH3                       CH3                                         H
                      O                         O                                         O
             N                        N                                           N
                                                    H N-demethylation                         H
                                                    OH                                        OH
Cl                N       Cl                N                       Cl                N




       Diazepam                 3-Hydroxydiazepam                          Oxazepam

f- Side chain oxidation :

                                                                         CH3

                                                      HOCH2                COOH
                          CH3
                                                    H3C
      CH3                   COOH
                                                                         CH3
H3C
                                                          CH3              COOH
                                                    HO
                                                    H3C




Oxidation involving carbon-nitrogen system

Nitrogen containing compounds divided into :

(1) Aliphatic         (2) Aromatic              (3) Amides

(1) Aliphatic amines
     a- Tertiary :
     The oxidative removal of alkyl group is carried by cyp 450 the reaction
is commonly referred as oxidative N-dealkylation.
     CH3                                    CH3CHO                               CH3CHO
               O              CH2CH3                              CH2CH3                          H
        NH C CH2 N                                            N                               N
                              CH2CH3                              H                               H
     CH3

    xylocaine (LA)                                    2ry amine                       1ry amine

   The initial step involve -carbon hydroxylation to form a carbinol-amine
intermediate, which is carbonyl moiety (aldehyde or ketone).

                                                      H
               R1     H                R1     O                       R1                  O
                    N C                     N C                            N H +
                                                 
               R2                      R2                             R2



b- Secondary (either parent compounds or metabolitis)

   Secondary amine are susceptible to oxidative N-dealkylation, oxidative
deamination and N-oxidation reaction.
                               O
                H                                         H
                              HCH                                          NH3                        CH3
                N                                         N
                    CH3                                       H
           CH3                                        CH3                                     O



  Methamphetamine                      Amphetamine                                  Phenylacetone

N.B. If -carbon hydroxylation can not occur, then oxidative deamination is
      not possible e.g. :


        Cl                             Cl

       NHCH3                           NH2
           O                            O



Ketamine                       Norketamine
N-oxidation not restricted to -substitute 1ry amine but also amphetamine N-
hydroxylation. e.g.:


                                     Cl                         Cl

                                 NH2                            NH OH
                                     O                           O



Hydroxylamine unstable further oxidized.
                                                                          O
                                                                     +
                             NH OH                N     O             N
                                                                          O-
                hydroxyl amine               nitroso            nitro

   Metabolic N-oxidation of secondary aliphatic amine and alicyclic lead to
N-hydroxylation often these hydroxylamine are susceptable to further
oxidation to nitrone.

                         H                            O H                      O-
                                 FMO                                      +
                     N                            N                        N
                         CH3                          CH3                      CH2
                ry
             2 Amine                      Hydroxylamine              Nitrone

         H5C6        O                     H5C6        O                  H5C6       O
                                FMO
                                                                                     +
          H3C        N                      H3C         N                     H3C    N
                     H                                 O                             O
                                                            H                        -
             Phenmetrazine            N-Hydroxyphenmetrazine                    Nitrone metabolite

c- Primary aliphatic amine are biotransformed by oxidative
    deamination or by N-oxidation.
N.B. Oxidative deamination of most exogenous primary amine (xenobiotic)
      is carried out by cyp 450, however endogenous primary amine. e.g.,
      catecholamine are metabolised by monamine oxidase (MAO) non
        microsomal oxidase enzyme in mitocondria.
                                                                                    O
                                         MAO
HO                  CH CH2 NH2                        HO                    CH C H
                    OH                                                      OH
     HO                                                    HO
          Epinephrine
 ALD-reductase
                         HO                 CH CH2OH
   NADPH
                                            OH
  as cofactor
                              HO

                         Ethylene glycol derivative

(2) Aromatic amine and heterocyclic :
Oxidative N-dealkylation as well as N-oxide formation takes place.
                                                            CH3
                                                            N O
                                     n
                                 atio
                              xid                           CH3
                           N-o
              CH3
          N
              CH3     ca                                                                O
                        rbo
                           nh                                                        HCH
                             yd
                               rox                                  CH3                           CH3
                                  yla
                                     tio                        N                             N
                                        n
                                                                    CH2OH                         H

                                                 Carbinol amine
Sec. aromatic amine

              CH2R                               CH2R                          CHR
          N          N-hydroxylation                    oxidation         +             H2O
                                             N                             N                  NHOH
              H                                  OH                            O-
 2ry amine                                                          nitrone

1ry amine
  NH2                     NHOH                        N O
Aniline                Hydroxyl amine           Nitroso

(3) Amides
     Amides are susceptible to oxidative N-dealkylation and N-hydroxyl-
ation reaction.

              CH3                               CH2OH                     O          H
                        O                            O                                       O
              N                                  N                      HCH          N


Cl                  N              Cl                N                          Cl       N




         Diazepam

     In case of cyclic amides or lactam, hydroxylation of alicyclic carbon  to
the nitrogen atom leads also to carbinolamides.

          H                                      H
                       CH2CH2Cl                                  CH2CH2Cl
     H    N                               OH    N
          O         N                           O            N
               P                                         P           CH2CH2Cl
                        CH2CH2Cl
                   O                                         O
Cyclophosphamide                        4-Hydroxycyclophosphamide

                                  4-Hydroxycyclophosphamide


                                                     H2N         CH2CH2Cl
                                           O
                                                 O               N
                                           CH            P           CH2CH2Cl
                                                         O
                                           Aldophosphamide
                                                          ox
                                                             id
                                                               at
                                                                 io
                                                                   n
                              H2 N                                             H2N     CH2CH2Cl
                  O                      CH2CH2Cl                 O
                                                                     OH
                             HO P    N                                 O               N
            HC CH +                                                C               P        CH2CH2Cl
            H2C                 O        CH2CH2Cl
                                                                                   O

        Acrolein             phosphoramide mustard                     carboxyphosphamide

N-Hydroxylation of aromatic amide :
    Occurs to a minor extent and this biotransformation pathway may lead to
chemically reactive intermediate.                   Acetaminophen is safe at therapeutic
doses. When large doses are ingested extensive liver necrosis is produced.
        O                                       O                                      O
H       C                              HO       C                                      C
    N       CH3                             N       CH3                            N        CH3
                                                               H2O
                  N-hydroxylation


                                            O                                      O
                                                H
Acetaminophen                 N-Hydroxyacetaminophen                   N-Acetylimidoquinone
                                                                                       GSH
                                                                          es




                                                                   r                    O
                                                                        ul




                                                                 ve
                                                                     ec




                                                              Li
                                                                  ol




                                                                               H        C
                                                                 m




                                                                                   N         CH3
                                                               ro
                                                             ac
                                                            M




            Liver necrosis           Covalent binding
                                                                                             SG
                                                                                   OH
                                                                       Glutathione conjugate

Oxidation involving carbon-sulfur system :
    Carbon-sulfur functional group are susceptible metabolic S-dealkyl-
ation, desulfuration and S-oxidation.
                                              O
                                                                                  O       O
          S                                       S                                   S
                                                                 

          N                                       N                                   N
                          CH3                                CH3                                     CH3
                      N                                  N                                       N
                      CH3                                CH3                                     CH3

     Chloropromazine                  Chloropromazine sulfoxide                       sulfones

Sulfoxide drugs metabolites may be further oxidised to sulfones.

      SCH3                             SCH3                                  SH
                                                             O
              N                               N                                       N
 N                                N                   - H C H           N
                                                                                              + HCHO
      N       N                        N      N                              N        N
              H                               H


-(methylthio)purine                                                6-Mercaptopurine

     Oxidative conversion of carbon-sulfur double bonds (C=S) thiono to
(C=O) is called desulfuration.
                          O                                                       O
              H5C2                                                    H5C2
                                  H                                                       H
CH2CH2CH2         C           N                       CH2CH2CH2        C              N

              CH3         N                                           CH3         N
                 O                S                                      O                O
                          H                                                       H

                  Thiopental                                         Pentobarbital




2- Reductive Reaction
     Reductive processes play an important role is the metabolism of many
compounds containing carbonyl, nitro and azo groups.
      Reductive pathways that are less frequently occur are:

Reduction of N-oxide to tert. amine

                                     R3N  O  R3N

Reduction of -CH=CH-  -H2C-CH2-

Reduction of sulfoxide to sulfides
                                 O
                       H3C S CH3                                 H3C S CH3
                  Dimethylsulfoxide                             Dimethylsulfide
                       (DMSO)

Reductive cleavage of disulfide linkage.
                            S                                                  S
            (C2H5)2 NC           S   S CN (C2H5)2                  (C2H5)2 NC      S H
                                         S
                           Disulfiram                          Diethyldithiocarbamic acid

Bioreduction of hydrated aldehyde to trichloroethanol.
                  OH                                     O                       OH
                                     - H2O                      ALd
            Cl3C C H                            Cl3C C                     Cl3C C H
                  OH                                     H     reductase         H
        Chloral hydrate                       Chloral

Bioreduction of nitro to amines:

              H                                                        H
                       O                                                       O
              N                                                        N
                                   Nitro reductase
O2N                N            and NADPH dependent      H2N               N
                                microsomal reductase
                       R                                                       R



R = Cl clonazepam                                        7-Aminometabolite
R = H nitrazepam

(NADPH) reduced nicotinamids adenosin dinucleotide phosphate form.

    The enzymatic reduction of azo compound is best illustrated by
conversion of prontosil to active sulfanilamide metabolite in liver.
                                  NH2

                     H2N            N N               SO2NH2




                                    prontosil


                          NH2

            H2N             NH2         +       H2N            SO2NH2


       1,2,4-triaminobenzene                     Sulfanilamide

3- Hydrolytic Reactions :
    Hydrolysis of ester and amides linkage in many drugs is catalyzed by
hydrolytic enzymes present in various tissues and plasma.

     The metabolic products formed, namely carboxylic acid, alc., phenols
and amines are polar and functionally more susceptible to conjugation and
excretion than the parent drug.

    Estrases enzymes for ester and amidases for amides are found in liver,
kidney, intestine.

ex. of ester hydrolysis
                     COOH                                 COOH
                            OCOCH3                               OH
                                                                      +    CH3COOH


   Aspirin (antipyretic analgesic)                 Salicylic acid
  O
                 “
                 N(CH3)3                     COOH
      O                     choline
                                                          +   2 HO            “
      O          “          esterase                                          N(CH3)3
                 N(CH3)3                     COOH
  O
  Succinylcholine                      Succinic acid              Choline base
(skeletal muscle relaxant)
           CH3                                        CH3
            N                                         N



                                                                 +        C2H5OH
            COOC2H5                                   COOH

Meperidine (narcotic analgesic)

ex., of amide hydrolysis phthalyl and succinyl sulfathiazol

          COOH

                                         N         amidase                                     S
          COHN               SO2NH                             H2N                 SO2NH
                                                 S in colon                                N

           COOH

                                                  S
           COHN                SO2NH
                                             N


Amides are slowly hydrolysed in comparison to esters.
                O               C2H5
H2N             C OCH2CH2 N
                                                       este                  COOH
                                C2H5             rapi      rase
                                                     d hy
                                                         drol
                                                             ysis

                                                        ase
                O                  C2H5            amid       sis
                                                          roly               NH2
H2N             C NHCH2CH2 N                           hyd
                                                  slow
                                   C2H5

Procainamide (antiarrhythmic)

      Many parent compounds are derivatised to generate prodrugs to
overcome some undesirable property e.g.: bitter taste or poor solubility or
irritation at site of injection.

      The presence of esterase enzymes in many tissues and plasma make ester
derivative logical prodrug candidates e.g. : Chloramphenicol palmitate to
overcome the bitter taste.

                    NHCOCHCl2
                                                   intestinal
O2N            CH CH2CH2O C         (CH2)14CH3                      Chloromphenicol
                                                   esterases
               OH             O



                            *******************

II- Conjugation Reactions (Phase II)
      Functionalization reactions do not always produce hydrophilic or
pharmacologically inactive metabolities. However, conjugation reaction are
capable of converting these metabolites to more polar H2O soluble inactive
products.

a- Glucuronic acid Conjugation :
      It is the most common conjugative pathway in drug metabolism for the
following reasons :
 1) Readly available supply derived from D-glucose.
 2) Numerous functional group that can combine enzymatically with
         glucuronic acid e.g. OH, COOH, NH2 or sulphur compound.
 3) Glucuronoid moiety with its ionized COO and polar OH when attached
         to substrate greatly increase H2O solubility.

     The reaction between the drug and uridine diphosphate glucuronic acid
(UDPGA) active form of glucuronic acid is catalysed by UDP glucuronosyl
transferases.

Ex: of glucuronidation pathways:
                                                    esterases
                                                                                     NHCOCH3



                                  NHCOCH3                               COO-

                                                                    H            O O
                                          UDP Glucuronosyl              H
                                              Transeferase              OH       H
                                                                HO                   H
                                  OH
                                                                        H        OH
                              Acetaminophen
                                  or

     COO -                  H3C        COOH
                                                                    COO         O           CH3
 H          O H
                                                                H           O O C
     H                                    UDP Glucuronosyl
                        +                                           H
     OH     H
                                              Transef erase         OH      H
HO              O UDP
                                                              HO                H                 CH3
                        H3C
     H      OH                                                                         +
                                                                    H       OH
                                                                                      UDP         CH3
                              CH3

UDP-glucuronate             Ibuprofen
                       or
                                                                           -                        OH
                       NH2                                            COO          H
                                                                 H             O N                       COOH
                                     UDP Glucuronosyl                 H
                                             Transeferase             OH       H
                                  OH                            HO                 H
                       COOH
                                                                      H        OH
                       PAS
     Glucurinoide can attached directly to carbon without prior functional-
ization e.g. in phenylbutazone contain active methylene.

N.B.: Xenobiotic can be a substrate for more than one metabolizing enzyme
e.g. PAS

                 NH2     Acylation or N-glucuronoid conjugation



                       COOH                Acyl or glycin or glucuronoid conjugation
                 OH     Glucuronoidation sulfation


                                                            Bu         O

                                                                      N
                                                        O        N


                                             n
    Bu       O                       a   tio
                             o   xid

             N                                                   OH
O        N
                           Glu
                         con curnid                              COO
                                                                       -
                            jug      e
                               atio
                                    n                       H          O
                                                                 H                     Bu       O
                                                                 OH    H
                                                         HO
                                                                                                N
                                                                 H     OH O                 N
                                                       phenylbutazone-C-glucuronoid
                                                               metabolite
b- Sulphate Conjugation:
      Conjugation with sulphate occures primarily with phenols and
occasionally with alc., aromatic amine and N-hydroxy compounds.

                                          NH2
                                                        OH                             -
                                                                                    OSO3
                                 N
                                               N
         O
-O SO                                                            sulfotransferase
  3      P    O   CH2            N        N        +                                    + PAP
                        O                                             enzyme
         OH
                                                        NHCOCH3                     NHCOCH3
              H2O3PO        OH

            PAPS                                                       O-sulphate conjugate
3`-Phosphoadenosine-5`-phosphosulphate                                      of acetaminophen

      The reaction between PAPS (active form of sulphate) and the drug
catalyzed by sulfotransferase enzyme.

                            HO           COCH3                -O SO         COCH3
                                                                  3
  NHCOCH3                            N                                  N

                                              sulfotransferase
                                                   enzyme

  OCH2CH3                            OCH2CH3                            OCH2CH3

Phenacetin          N-hydroxyphenacetin                           O-suphate conjugate
                                                             of N-hydroxyphenacetin

c- Conjugation with amino acids:
      The amino acide glycine and glutamine are utilized by mammalion
systems to conjugate carboxylic, particulary aromatic acids.
      In contrast with glucuronic acid and sulphate, glycin and glutamine are
not converted to activated coenzymes. In stead the carboxylic acid substrate
activated to acyl CoA thioester.
e.g.: Benzoic acid to its glycin conjugate.
                                                                          O       NHCH2CO2H
    COOH                                                                      C


                                              acyl synthetase
           +        H2NCH2CO2H

Benzoic acid          Glycine                                      Hpippuric acid
O       NHNH2                                              O           NHCH2CO2H
    C                             COOH                         C

               Amidase
           hydrolysis
    N                             N                            N

 INH                           INA                Glycine conjugate
Isoniazide anti T.B.

                                                                              COOH
    CH2COOH           CH2COSCoA                                CH2CONH CH CH2CH2CONH2

                                      Glutamine
           +
                                  N-acyltransferase

Phenylacetic Acyl CoA thioester                      Glutamine conjugate of
   acid                                              phenylacetic acid

d- Acylation Reaction:
     Acylation contitutes an important metabolic route for drugs containing
1ry amino group.
e.g. Anticonvolsant clonozepan and nitrazepam.

                H                                     H                                       H
                         O                                         O                                  O
                 N                                     N                                      N
                                                                         N-acyl
                             nitroreductase                            transferase

O2N                  N                 H2N                     N                                  N
                                                                           CH3COHN

                         R                                         R                                  R



R = H, nitrazepam                     7-Amino metabolite                  7-Acylated metabolite
R = Cl, clonazepam
                               C2H5                                                  C2H5
                                       acetyl CoA
H2N             CONHCH2CH2 N                           CH3COHN        CONHCH2CH2 N
                                      transacetylase
                               C2H5                                                  C2H5


           Procaineamide                                  N-Acetylprocaineamide
                                                                   (active)

e- Methylation reaction:
      Methylation reaction plays an important role in inactivation of numerous
active catecholamines.

                                  COMT
HO               CHCH2NH2                           HO           CHCH2NH2
                OH                                               OH
      HO                                               H3CO

      Norepinephrine                                Normetanephrine
COMT = Catechol-O-methyl-transferase

      Methylation does not lead to polar or H2O soluble metabolite except
when create quaternary ammonium derivatives.
                                       ***********
                                        *********
                                          ******

Factors Affecting Drug Metabolism

      The rate of drug metabolism is important for its pharmacological action
as well as its toxicity slow rate lead to longer duration and accumulation of
the drug and rapid rate lead to rapid elimination and inactivation of the drug.

      Many factors affect drug metabolism these include: age, species, genetic
or heredity factors, sex, enzyme induction, enzyme inhibition and
pharmacodymanic factors.

a- Age differences:
   In most newborn animal, undeveloped or deficient oxidative and
conjugative enzyme are chiefly responsible for the reduced metabolic
capability. An illustration of the influence of age on drug metabolism is
seen in duration of action of hexobarbitol in newborn and adult mice when
given in dose 10 mg/Kg body weight the newborn sleep more than 6 h., and
adult sleep for 5 min.

            O                               O                                 O
     H3C            CH3            H3C              CH3                 H3C           CH3
                N                               N                                 N

      O     N       O               O       N       O                    O    N       O
            H              HO               H                       O         H
 Hexobarbital             3`-Hydroxyhexobarbital                    3`-Oxohexobarbital

                                                    O
                                         H3C                CH3
                                                        N

                                           O        N       O

                                    O             H
                                         glucuronide


b- Species and strain:

   Different species may biotransform drugs by similar or different
pathways.

                                                                              COOH
                                                                O
                                                        CH2 C CH3
                                   it
                                 bb
                               Ra
                            n,      g
                CH3       Ma inapi
           CH2 CH NH2        gu

                             Ra
                               t                                        CH3
                                             HO                     CH2 CH NH2
                                         p-Hydroxyamphetamine
                                         (aromatic hydroxylation)




c- Hereditary or Genetic Factors:
   Genetic or hereditary factor are mainly responsible for the large
differences of drug metabolism.
e.g.: Metabolism of INH anti T.B. occurs primarily by N-acylation.

               O       NHNH2                     O       NHNHCOCH3
                   C                                 C

                          N-acetyl transferase

                   N                                 N

              INH
   Studies indicate that the individual differ in ability to acylate the drug
either slowly or rapidly.      Rapid acylator have more hepatic N-acetyl
transferase enzyme.
   Eskimos and oriental are rapid acylator.               Whereas, Egyptian and
Mediterranean are slow acylator.

d- Sex difference:
   The rate of metabolism varies according to sex.              Adult male rats
metabolize several drugs at a much faster rate than female.                 e.g.
Hexobarbital oxidation.

e- Enzyme Induction:
   The activity of hepatic microsomal enzyme eg. cytochrom P-450 mixed
function oxidase system can be markedly increased upon exposure to
polycyclic aromatic hydrocarbon.
   The enzyme induction lead to increase the rate of drug metabolism and
decrease the duration of action. e.g. Inducing agent phenobarbital inhances
metabolism of acetaminophen and coumarin anticoagulant.


f- Enzyme Inhibition:
   Several drugs capable of inhibiting drug metabolism lead to drug
accumolation and prolongation of action and serious adverse effects.

   The metabolism of phenytion is inhibited by chloramphenicol and INH.

N.B. Enzyme inhibition can occur by heptotoxicity leading to impairment of
      enzyme activity.

g- Dietary factors:
   Protein/carbohydrate ratio in the diet affect the metabolism of few drugs.

h- Physiologic factors:
   Such as pathologic states of the liver and harmonal disturbances
(thyroxime, steroids) markedly affect drug metabolism.

i- Pharmacodynamic factors:
   Dose, frequency and route of adminstration and protein binding of the
drug affect its metabolism.
                               Diagnostic agents




      Diagnostic agents are compounds used in diagnosis to detect impaired
function of the body organ and to recognize abnormalities in tissue structure,
these agents applied directly to the body.         Some clinical diagnostic
chemicals used to determine normal and pathologic products in urine, blood
and other body fluids or tissue staining dye for microscopic examination.

Factors that often determine the usefulness of diagnostic agents are:
 1     chemical composition
 2     Solubility
 3     Metabolism
 4     Rate of excretion.

Classification of Diagnostic Agents:

I- a- Radioopaque for radiography.

     b- Radiopharmaceutical for scintigraphy.

II- Compounds for testing functional capacity.

III- Compounds modifying a physiologic action.

I- Radioopaque for radiography

     Roentgent’s X rays and computed tomography.
      In conventional roentgen examination tissues are visualized according to
their ability to attenuate a beam of X-rays before strike a detector. The
attenuation varies according to the relative density of the tissue. Bone
absorbs large percentage of the rays appears white on the exposed film. The
air filled lung is translucent relative to bone and appears darker on the
exposed film.

     Depending on the relative opacity of radiopaques to X-rays. Substances
that increase the density of a tissue, thereby rendering it opaque to x-rays are
called positive contrast agents.

     Radiopaque DA include organic and inorganic compounds which have
the property of casting a shadow on X-ray film.

     Barium sulphate is the most inorganic compounds that often used as
suspension in roentgraphic (X-ray) examination of gastrointestinal tract.

Organic iodinated radiopaque:
     I2 in strong covalent linkage. I2 was observed to contribute opacity to x-
ray. They are more opaque and used by two mean:

1) Systemic
     Adminstred orally or IV to examine kidney (urography) or liver
(cholecystography) for visualization of renal cavities, ureter, biliary tract,
blood vessels.

Precausion:
 1 Prelimenary test for sensitivity.
 2 Cathartic given the night before the injection.
 3 Food, liquids withhold for at least 18h., to prevent blurring of the
     picture.
 4
   4)

2) Retrograde method
   Introduction of diognostic agent by mechanical means into bladder, ulcer
area or urethra by cystoscop through Catheter.

Water soluble organic iodinated radiopaque

Diatrizoate sodium (HypaqueR)

                                       COONa
                                  I          I


                          CH3COHN            NHCOCH3
                                       I


sodium-3,5-bis(acetylamino)-2,4,6-triodobenzoic acid, as solution orally and
injection used in urographic studies (urinary tract).

Ipodate Sodium (OragrafinR)

                                  CH2CH2COONa
                             I          I

                                                 CH3
                                       N     N
                                  I          CH3


Sodium-3-[[(dimethylamino)methylene]amino]-2,4,6-triiodohydrocinn-
amate.
Orally as capsule
Cholecystography (gallbladder)

Maximum concentration in the hepatic and biliary ducts occurs in 1-3 h., and
persists for about 45 min. Cholecystopexy is any gallblader disease and to
aid in diagnosing the disease a compound is desirable that is opaque to x-ray
and well concentrated in the gallbladder and the bile duct.

Water insol. organic iodinated radiopaque
Iopanoic acid (TelepaqueR)
                                                   C 2H 5

                                                       COOH
                                   I                      I


                                                       NH2
                                               I


3-Amino--ethyl-2,4,6-triiodohydrocinnamic acid
- Orally
- Diagnosing gallbladder and bile duct.

Iocetamic acid (CholebrineR)
                                       O              CH3
                                                      CH COOH
                             H3C           N
                               I                      I


                                                      NH2
                                           I


N-Acetyl-N-(3-amino-2,4,6-triiodophenyl)--aminoisobutyric acid

Administered orally 10-15 h., before x-ray film of the gall bladder.

II- Compounds for Testing Functional Capacity

  A- Agents for kidney function test
   Aminohippurate sodium IV injection, sensitive to light, we add sod.
bisulfite to prevent darkening of the solution.
                            H 2N              CONHCH2COONa




Synthesis

O2N              COCl    + H2NCH2COOH        - HCl
                                                         O2N           CONHCH2COOH



1- red.
          H2N              CONHCH2COONa
2- equiv.
   NaOH


      The sodium salt is excreted by tubular epithelium of the kidney and by
glomerulus thus determining the functional capacity of tubular excretary
mechanism.

Indigo Carmine, IV injection
                                         O       H
                        NaSO3                        N

                                        N                      SO3Na
                                         H       O

                                Indigotindisulfonate sod.
                         5,5`-Indigotindisulfonate disodium

      For determination of renal function and to locate the uretheral orifices, it
appear in urine after 10 min.

B- Agent for liver function test
Sulfobromophthalein (BromosulphaleinR)
                                                   OH
                              NaO3S
                                                                      OH
                                         Br
                             Br
                                                                      SO3Na
                                                        O
                             Br
                                         Br         O

            4,5,6,7-Tetrabromo-3`,3``-disulfophenolphtholein disodium
     The compound taken parentally and removed through liver, the amount
remained in blood measured colourimetry after certain time interval.

     The rate at which the dye removed from blood is a measure of hepatic
function.

Rose Bengal
                                               I                 I
                                   + -
                                  NaO                   O                O


                                    I                                    I
                                              Cl                 COONa


                                              Cl                 Cl
                                                        Cl


                         Tetraiodotetrachlorofluorescein
       Cl       O
Cl                           HO                    OH
                                                              reaction
                O    +   2                                                    tetrachlorofluorescein
                                                            condensation
Cl
                O                                                                       Iodination
       Cl
                                                                                   Rose Bengal




Used as a test for liver function injected in saline intravenously and the liver
almost remove the dye from blood stream a normally functioning liver will
remove 50% of the dye within 2 min.

The dye and patient receiving it should be protected from light.

Radiopharmaceutical
    Neutron and protons (mass of atom) exist in well-defined energy levels
in the nucleus held together by strong forces.
    They have a particular ratio, an excess of either proton or neutron results
in an unstable nucleus state and an energy state other than the stable state
which will spontaneously transform itself into stable one. This phenomenon
of spontaneous nuclear transformation to attain stability is always
accompanied by a release of energy and is called (radioactivity).

    Atoms with the same number of proton and different number of neutron
are called (isotopes).

    The energy released from radioactive is usually detected by its ability to
ionize the atom of matter through which it passes.

    The Rad is a quantitative measure of radiation energy absorption which
usually called the dose.

    The nuclides used in radiopharmacentical (radioisotope tracer) must
have suitable short half-life and high yield of -rays (50-500 KeV) without
causing excessive tissue irradiation from other emission (e.g. from high
energy  particles).

    Many radionuclides may be used as scanning agents for organ or tumors
visualization. Scanning with radionuclides not only gives an indication of
the size, shape and position of an organ and aids in the detection of tumors,
cysts or abscesses but also allow assessment of the blood supply and the
specific function of the organ.

   The official pharmacopoeia recognize the following radiopharma-
ceuticals in various dosage forms and diagnostic aids Co57, Co58 in
pernicious anaemia I131, Cr51. Blood volume determination P32, Au198 in
chemotherapy as antineoplastic.

Radionuclide and radiopharmaceuticals for organ imaging
   The ideal radionuclide should be readily incorporated into carrier
molecules. The principal instrument for displaying images is the gamma
camera. These images may be planer or tomographic. I131 is the most
frequently used radionuclide of I2 in organ imaging radiopharmaceuticals it
is readily incorporated into a variety of organic molecules.

Technetium 99m
   It used to visualize thyroid and brain stable in water as either
pertechnetate anions TcO4- or insoluble technetium oxide (TcO2).           The
following chelate of Tc in which the organic moiety retains the physiologic
capacity to enter the enterohepatic cycle while it remains bound together
with the technetium.

Tc-99m     labeled     dimer   of   N-(2,6-dimethylphenylcarbamoylmethyl)-
iminodiacetic acid (HIDA).
                                        R

                               O        N        O
                                    O        O
                                        TC
                                    O        O
                               O        N        O

                                        R


   To be usual as an organ imaging agent, radiopharmaceutical must be
able to localize selectively in a particular organ or tumor. Usually, a 10 fold
difference in uptake of radioactivity by the target agent versus surrounding
nontarget areas is sufficient for imaging purposes.



Brain imaging
    Most intracranial lesions alter the blood brain barrier so that various
radiopharmaceuticals can penetrate inaccessible regions and localize in and
around the lesion.

    The most commonly used agent for brain imaging is Tc-99m. Other
radiopharmaceuticals have become available that are sufficiently lipophilic
to available the blood brain barrier.

e.g. IMP and HIPDM
                                                    H
                                                    N     CH3

                           123
                                                  CH3   CH3
                                 I

                                             IMP
                     N-Isopropyl-[I123]-p-iodoamphetamine

                                     OH
                        H 3C                                  CH3
                                              N           N
                                              CH3         CH3

                                     I123

                                            HIPDM
N,N,N`-Trimethyl-N1-[2-hydroxy-3-methyl-5-iodobenzyl]-1,3-propane-
diamine

				
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