药物代谢动力学

Document Sample
药物代谢动力学 Powered By Docstoc
					第二章 药物代谢动力学
Pharmacokinetics
             Locus of Action       Tissue Reservoirs
              “receptors”
         Bound           Free      Free         Bound



                    Systemic
                    Circulation
Absorption                  Free drug                   Exceretion

                   Bound drug           Metabolites




                          Transformation
Manners of Transport Across Membrance

             Passive transport

           Across    Across    Carrier-
           membrane aqueous    mediated
           and lipid channel   transport
 Outside




 Inside
             Routes of Drug Administration
Enteral
   within or by way of the GI tract
      Oral (PO), rectal, sublingual
Parenteral
   Not within the alimentary canal
     Inhalation, IM, SC, IP, topical
Central
   Into the brain or spinal cord
   Intrathecal
Routes of Drug Administration
            common abbreviations…
PO = per os = oral

IV = intravenous = into the vein

IM = intramuscular = into the muscle

SC = subcutaneous = between the skin and muscle

IP = intraperitoneal = within the peritoneal cavity

icv = intracerebroventricular =
             directly into the ventricle of the brain
Factors Affecting Response to Drugs
                Dosage
       Route of Administration
          Rate of Absorption
         Rate of Elimination
 Physiochemical properties of the drug
  age, sex, species, metabolism, etc…
                             尿pH值对药物排泄的影响

                苯巴比妥[弱酸性药] (狗)                            苯丙胺 [弱碱性药] (人)
       50
                                                     40
                                              计                     精神反应
           40                                 分 20                             酸性尿
                         碱性尿                  值
  清                                                                           (pH~5)
                         pH 7.8-8.0                  0
  除                                                  2                         碱性尿
    30                                                           血浆药物浓度
  率                                                                           (pH~7)
(ml/min)                                             1
                                             m
           20                                M
                                                      0
                                 酸性尿                 30
                                                                    尿排泄量
           10                    pH<7
                                                     15
                                            mmol/h
           0                                          0
                0    2       4     6    8                 0   1 2 3 4 5 6 7
                    排尿(ml/min)
   口服和静脉注射阿司匹林659mg后的时-量曲线
    10


  血 8
  浆
  阿
  司 6
  匹
  林
  浓 4
  度
(mg/L)
     2



     0
         0   20   40      60     80   100   120
                       时间(min)
血                  MEC
药
浓
度



                             C

                             A

                             B




              时间
            三种不同的生物利用度
    A.吸收速度快、吸收量完全
    B.吸收速度与A相同,但吸收量仅为A的50%
    C.吸收量完全,但吸收速度为A的50%
               四种由不同药厂生产的相同剂量地高辛片剂的生物利用度




           2
  血
  浆
  地
  高
  辛
  浓        1
  度
(nmol/L)




               0   1    2       3   4   5
                        时间(h)
      Elimination kinetics
1. First-order elimination kinetics
                多次给药的时-量曲线
    2
                        Css.max


药
物
浓
度                                 Css.min
    1

                             稳态浓度




    0
        0   1   2   3   4     5         6   7
                      三种不同给药方案对稳态浓度的影响
                      A. 缩短给药时间 B. 增加给药剂量 C. 负荷量给药



              A                             B                            C


血   300                            300                          300
药                                                                                MTC
浓
度   200                            200                          200


    100                            100                          100              MEC

     0                              0                            0
          0       2    4   6   8        0       2   4   6   8        0       2   4   6   8


                                            时间(半衰期)
2. Zero-order elimination kinetics
Pharmacokinetic Evaluation of
Gepirone Immediate-Release Capsules
and Gepirone Extended-Release
Tablets in Healthy Volunteers




JOURNAL OF PHARMACEUTICAL SCIENCES,
    VOL. 92, NO. 9, SEPTEMBER 2003
•Gepirone is a 5-HT1A agonist for
the treatment of major depression.

•half-life of 3 h and good oral
bioavailability, and undergoes
extensive first-pass metabolism
•Because of its rapid absorption and
short half-life, the gepirone-IR
(immediate-release formulation) must be
administered at least twice daily.

•This regimen results in high peak
concentrations and marked peak-to-
trough fluctuations in plasma
concentrations.
•These fluctuations may contribute to an
 increased incidence of adverse events,
such as nausea, dizziness, headache, and
somnolence, and have the potential to
result in lower patient compliance and
reduced effectiveness.

•extended-release gepirone
formulation(ER)
immediate-release formulation(IR)
Figure 1. Mean gepirone plasma concentrations
following administration of gepirone-IR formulations
(10mgq12 h,n=12) or gepirone-ER formulations (ER-1:
20 mg q24 h, n=12; ER-2: 20 mg q24 h, n=12; ER-3:
25 mg q24 h, n=12).
Figure 2. Mean 1-PP plasma concentrations following
administration of gepirone-IR formulations
(10 mg q12 h, n=12) or gepirone-ER formulations (ER-
1: 20 mg q24 h, n=12; ER-2: 20 mg q24 h, n=12; ER-3:
25 mg q24 h, n=12).

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:2
posted:2/3/2013
language:Latin
pages:22