Biochemistry - Distribution Renal Elimination by jpl7986

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									            Drug distribution: Compartments


Intracellular volume      Interstitial volume (15% body weight)
(40% body weight)



                                           Intravascular volume
                                           (5% body weight)




        Body fat (several % body weight)
Factors affecting the equilibrium distribution
     of drugs across the compartments


1. Membrane-impermeant drugs will be excluded from the
   intracellular volume (Example: Lithium)
2. Lipophilic drugs will be enriched in the fat tissue
   (example: Thiopental – see later)
3. Drugs with a high degree of protein binding will be more
   concentrated in the plasma (the intravascular volume) than
   in the interstitial fluid
 The ‘volume of distribution’
       Amount of drug in the body
Vd =
       Drug plasma concentration


          Lipophilic drugs: Vd > total body volume



          Extracellularly confined drugs:
          Vd < total body volume


          Intravascularly confined drugs:
          Vd << total body volume
                     Protein binding




•   Protein binding is largely determined by the hydrophobicity
    of the drug molecule
•   Main carrier protein in blood plasma is albumin
 Kinetic aspects of drug distribution: Thiopental
                         O
                             CH3                     100   Fractional
                     H
                     N                                     distribution
                 S                   CH3                   (%)
                     N         CH3
                     H                               80
                         O



                                                     60
                                                             Blood

                                                             Brain
                                                     40
                                                             Lean tissues

                                                     20      Fat



                                                     0
0.1          1               10            100    1000
      Time after intravenous application (min.)
          Drug elimination (1): Kidney

Typical pathways:           Hydrophobic drug molecule



Hydrophilic drug molecule             Liver



         Kidney             More hydrophilic metabolite



         Urine
Anatomy of the kidneys and urine excretion organs
                    Kidney function
Urine is ‘distilled’ from blood plasma in several stages:

1. Filtration: The kidneys are perfused at a rate of ~1.2 l/min.
   Approximately 10% of the plasma volume is squeezed
   across a filtering membrane that retains most
   macromolecules but lets through small molecules
2. Re-absorption: Most small solutes – glucose, salts, amino
   acids – are taken up again by specific transporters. Water
   is recovered by the ensuing osmotic effect. Some solutes
   are partially or totally excluded from reuptake
3. Some substrates are actively secreted from the blood into
   the nascent urine
Kidney structure: Glomerulus and tubuli
The nephron
The nephron




              Filtration




              Reuptake

              Secretion
      Primary filtration in the glomerulus (1)

                       Bowman’s capsule

  afferent arteriole
                                          proximal tubule




efferent arteriole
         Primary filtration in the glomerulus (2)




                             Primary filtrate


Basal membrane
                                                    Blood
Endothelial cell with
fenestrations

Podocyte pseudopodia
                              Filtration slits
             Segments of the nephron
proximal convoluted tubule distal convoluted tubule




proximal
straight                                              collecting
tubule                                                duct

thin descending    Loop of
limb               Henle
                                thin ascending
                                limb
    Segments of the nephron and their functions

           Active secretion of uric acid, Reuptake of weak organic
Filtration organic acids, organic bases acids and bases




  Reuptake of
  glucose, amino
  acids,                             Reuptake of
  bicarbonate, …                     salts and
                                     water
                    Excretion of membrane-permeant versus
                          non-permeant molecules (1)

                    Residual volume   permeant         non-permeant
Flow along tubule




                                          c=constant       n=constant
Excretion of membrane-permeant versus non-
           permeant molecules (2)

  Concentrations                Fractions retained in
                                filtrate




               Traveled tubule length


             permeant         impermeant
         Forced diuresis for accelerated
             elimination of poisons
Flow along tubule
         Primary filtration in the glomerulus (2)




                             Primary filtrate


Basal membrane
                                                    Blood
Endothelial cell with
fenestrations

Podocyte pseudopodia
                              Filtration slits
The volume flow rate of glomerular filtration


 •   The glomerular filtration rate is the major determinant
     in the rate of excretion of polar solutes
 •   The glomerular filtration rate shows substantial
     variation with age and can be substantially reduced in
     patients with prior kidney disease
  We need to measure it
      Measurement of the glomerular filtration rate
             using the inulin ‘clearance’

Plasma concentration
= filtrate concentration




          Urine concentration, flow rate

                                              Urine concentration
GFR = Inuline clearance = Urine flow rate 
                                              Filtrate concentration
    Active secretion of p-aminohippurate in the
                  proximal tubule
Tissue                                            Tubule
 +++                                             +++
                       ---
p-AH-                                            p-AH-
                a-Ketoglutarate--,               Cl-, HCO3-,…
                other divalent anions



                                O
                                             O
         p-AH   H2N                 N
                                    H
                                        C
                                        H2
                                             O
p-Aminohippurate clearance measures renal
             plasma flow



               Renal plasma flow = pAH clearance =


                                   Urine concentration
               Urine flow rate 
                                   Filtrate concentration
 Probenecid inhibits tubular secretion of penicillin



penicillin                                                            penicillin
                          a-Ketoglutarate--                           Cl-, HCO3-,…
                                                                probenecid



                  O                CH3
                               S                               O             O
                                                   C3H7
             C        N                  CH3
             H2       H                                   N    S
                           N
                                                   C3H7                      O
                      O                  C     O               O

                                         O

         penicillin G                                         probenecid
  The extent of a drug’s reuptake in the distal
 tubule depends on its membrane permeability
                       Protein-bound (%)               Clearance (L/h) Half-life (h)

Cimetidine                        19                           32             2

Phenobarbital                     51                           0.25           98


  H3 C            C    S   C    C    N   C   N   CH3
                  H2       H2   H2   H       H
         HN   N                          N                    Cimetidine
                                             C   N


                       O
              H
              N

         O                                                    Phenobarbital
              N            C2H5
              H
                       O
 Drug reuptake may vary with urine pH:
          LSD as an example


        O   C   N              O   C   N




                                       +
                N                      N
                                       H




                          +
   N                     N
   H                     H2




Neutral or alkaline pH        Acidic pH

								
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