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浙江大学医学院基础医学系 • 汤慧芳

Section Ⅵ. Pharmacological Basis of Therapeutics. 药物治疗学基础. 浙江大学医学院基础医学系 • 汤慧芳. Chapter 2 Pharmacokinetics. Part 1. Drug transportation across cell membrane Part 2. The process of drug in body Part 3. Pharmacokinetics process. Part 1. Drug transportation across cell membrane.

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浙江大学医学院基础医学系 • 汤慧芳

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  1. Section Ⅵ. Pharmacological Basis of Therapeutics 药物治疗学基础 浙江大学医学院基础医学系 •汤慧芳

  2. Chapter 2Pharmacokinetics Part 1. Drug transportation across cell membrane Part 2. The process of drug in body Part 3. Pharmacokinetics process

  3. Part 1. Drug transportation across cell membrane

  4. 1. Classification of pharmacokinetics process (药动学过程的分类) ①Absorption(吸收) ②Distribution(分布) ③Biotransformation(生物转化) ④Excretion(排泄) ① + ② + ④ = transportation(转运) ③ + ④ = elimination(消除) ② + ③ + ④ = disposition(处置)

  5. 2. Transportation of drugs (药物的转运)The patterns of drug transportationacross cell membrane:

  6. Mechanisms of drug permeationA: filtration: tight junctionsB: lipid diffusion: through lipid cell membranes C: carrier-mediated transport: transported by carriers into or out ofcells D: membrane moving transport: endocytosis,and exocytosis.

  7. Characteristics ofsimple diffusion:●need not carrier(不需要载体);●don’t consume energy(不耗能);●no saturation(无饱和现象);●no competitive inhibition(无竞争性抑制);●to dynamic equilibrium finally(最终保持在动态稳定水平). 3. Passive transportation(down hill) (1)Filtration(滤过)—along pressure gradient) (2)Simple diffusion(简单扩散)—along concentration gradient)

  8. The factors affectingsimple diffusion ●difference of drug concentration; ●lipid solubility of drug. lipid solubility of drug  ionizability of drug  pKa of drug, and pHof solution. ion trapping(离子障)

  9. Handerson-Hasselbach’ Formula Weak acid drug: HA H+ + A– [H+] [A–] Ka = [HA] [HA] [H+] = [A–] Ka log [HA] / [A–]= log [H+] – log Ka = pKa – pH When pH = pKa, [HA] = [A–] pH ＞pKa, [HA] ＜[A–] pH ＜pKa, [HA] ＞[A–]

  10. log [HA] / [A– ]= pKa – pH Effect of pH on ionization of Salicyclic acid(水杨酸, pKa=3) pHlog [HA] / [A–] [HA] / [A–]non-ionized(%) (pKa – pH) 13–1= 2 100/199.0 23–2= 1 10/190.0 33–3= 0 1/150.0 43–4= –1 1/1010.0 53–5= –2 1/1001.0 63–6= –3 1/10000.1

  11. Fig. Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood. In the hypotheticalcase illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane, but the total concentration (charged plusuncharged) in the urine (more than 10 mg) is 25 times higher than in the blood (0.4 mg).

  12. Weak base drug: BH+ H+ + B [B] [H+] Ka = [BH+] [B] Ka = [BH+] [H+] log [B] / [BH+] = log Ka – log [H+] = pH – pKa When pH = pKa, [B] = [BH+] pH ＞pKa, [B] ＞[BH+] pH ＜pKa, [B] ＜[BH+]

  13. Clinical significance: ▲口服药物, 在胃肠道吸收, 弱酸性药物在酸性环境的胃中容易吸收, 弱碱性药物在pH 较高的肠道内容易被吸收. ▲▲改变尿液的酸碱度可以影响药物在肾小管的重吸收过程. 弱酸性药物在酸性尿液中容易重吸收, 因此减少了该药物在尿液中的排出, 而弱酸性药物在碱性尿液中则重吸收减少, 可增加该药物的排出量. 这一知识在临床上可以用于治疗某些药物中毒. 如催眠药苯巴比妥(酸性药物)过量中毒时, 用NaHCO3 静脉滴注, 使尿液碱化, 可减少苯巴比妥的重吸收而加速其排泄.

  14. 4. Active transportation(up hill)—— adverse concentration gradient transportation Characteristicsofactivetransportion: ●need carrier; ●energy consumption; ●saturability; ●competitive inhibition by congeners; ●active transport stop when no drug at one side of membrane.

  15. Part 2. The process of drug in body

  16. 1. Absorption (1)Enteral ingestion(胃肠道给药) ●oral administration(per os, po) ▲Site of absorption ▲first-pass elimination(首过消除) ●sublingual(舌下含服) ●per rectum(直肠给药) (2)Parenteral administration ●Intravenous(iv) —— no absorption. ●Intramuscular(im), ●Subcutaneous(sc), ●Other administration ▲inhalation(吸入):aerosol; ▲transdermal administration(透皮给药)

  17. 2. Distribution Factors affecting distribution: ① Regional blood flow, redistribution ② Physicochemical properties of drug: MW, LS, polarity,   ③ Selectivity of drug distribution: e.g. iodine(碘)  thyroid(甲状腺) ④ Biological barriers Blood-brain barrier(血脑屏障) Placenta barrier(胎盘屏障) Blood-eye barrier(血眼屏障) ⑤ Plasma protein binding of drug

  18. Plasma protein binding rate(PBR, 血浆蛋白结合率)Free typeBinding type Free type: ●Activity, ● Can be transported. Binding type: ●Reversible; ●Inactive temporarily; ●Cannot pass through membrane passively; ●Saturability and competition.

  19. Phase I and phase II reactions, and direct elimination, in drug biodisposition. Phase II reactions may also precedephase Ireactions. 3. Biotransformation(1)

  20. 3. Biotransformation(2)

  21. 3. Biotransformation(3) (1)Phase of biotransformation ●Phase I : Oxidation, Reduction, Hydrolysis Most case:inactivation or detoxification Some case: activation  or toxicity  activation : cortisone hydrocortisone phenacetin acetaminophen (非那西丁) (对乙酰氨基酚) toxicity : para-phenetidin (对氨基苯乙醚)

  22. ●Phase II : Conjugation with glucuronides, or glycine, or acetyl, or sulfate, et al.)  Solubility  Excretion from kidney

  23. (2)Hepatic microsomal enzymes(肝微粒体酶, hepatic drug-metabolizing enzymes, 肝药酶) Cytochrome P450 enzymes(细胞色素P450),includingoxidases, reduc-tases, hydrolases and conjugases. The characteristics of P450: ● low selectivity(选择性低); ● high variability(变异性大): ● Enzyme induction(酶诱导) & Enzyme inhibition(酶抑制).

  24. Enzyme induction(酶诱导) & Enzyme inducer(酶诱导剂)Phenobarbital(苯巴比妥),Rifampin(利福平), et al. Enzyme inhibition(酶抑制) & Enzyme inhibitor(酶抑制剂)Chloramphenicol(氯霉素),Isoniazid(异烟肼),Cimetidine(西咪替丁),et al.

  25. (3)Other drug metabolism enzyme: ●Non-microsomalreductiveenzymes(非微粒体还原酶, in hepatic cell), ●Esterase(酯酶, in plasma), ●Acetification enzyme(乙酰化酶, in cell liquid), et al.

  26. 4. Excretion (1)Renal excretion: including ●glomerular filtration, ●tubular secretion, ●tubular reabsorption factors influencing renal excretion urinary flow, urinary pH.

  27. (2)Biliary excretion:tetracycline(四环素), rifampin (利福平), erythromycin(红霉素) ★hepato-enteral circulation:digitoxin(洋地黄毒苷) (3)Other excretion routes: lung, saliva, milk, sweat, et al.

  28. Part 3. Pharmacokinetics process (rate process) • 1. Concentration-time relationship (药物浓度-时间关系, 时量关系) and concentration-time curve(药物浓度-时间曲线, C-T curve, 时量曲线) • Tmax: 达峰时间, • Cmax: 高峰浓度, • AUC: 曲线下面积(area under curve).

  29. 1. latent period 2. persistent period (持续期); 3. residual period (残留期) (潜伏期); MTC Cmax Tmax (Tpeak)

  30. 2. Kinetics of drug elimination(药物消除动力学 —— 速率类型) dC = - keCn dt C : concentration t : time ke: constant of elimination rate n=1:first-order kinetics elimination n=0:zero-order kinetics elimination

  31. FIGUREComparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units perhour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant andindependent of concentration. 恒量消除 恒比消除

  32. (1)First-order kinetics elimination (一级动力学消除, 恒比消除) d C = – keC1 dt d C = – Ke C dt d C = – Kedt C Ct = C0 e- ket log Ct = log C0 –ke/2.303 t

  33. log Ct = log C0 -ke/2.303 t log CC log C0 0t slope = -ke/2.303 0 t

  34. log Ct = log C0 -ke/2.303 t t = 2.303 / ke (log C0 - log Ct) if: Ct = ½C0:t½为半衰期 t½=2.303 / ke• log 2 = 0.693 / ke ke = 0.693 / t½ ① Constant fraction is eliminated per unit time; ② log C - t curve is a straight line, the slope is -ke/2.303 ; ③ t½(半衰期) is constant, =0.693/ke; (be continued)

  35. ④once input drug(A), after 5 t ½, 96% of A is eliminated.

  36. (2)Zero-order elimination (零级动力学消除, 恒量消除) d C C = - kC0 d t = - k0 d C = - k0 dt Ct = C0 – k0t 0 t ① Constant amount is eliminated at maximal capacity per unit time; ② C-t curve is a straight line, its slope is -k; ③ t½ is not constant. K t½ = C0―(½C0) = ½C0 = 0.5C0 t½= 0.5 C0/K

  37. (3)Michaelis-MenteneliminationPhenytoin(苯妥英),Salicyclic acid(水杨酸)… dC Vmax• C = – dt Km + C When C is very low, Km＞＞C: 一级动力学 dC Vmax• C = – = – Ke C dt Km When C is very high, Km＜＜C: 零级动力学 dC Vmax• C = – = – Vmax =– K0 dt C

  38. 3. Pharmacokinetics model(药动学模型): Compartment model(房室模型) (1)one-compartment model Drug absorption elimination

  39. Log C one-compartment model 32 16 8elimination curve 4 2 C = C0 e-Ket 1 0 1 2 3 4 5 6 t1/2

  40. (2)two-compartment model Central compartment Drug elimination absorption Peripheral compartment

  41. log C ATwo-compartment model C =Ae-t + Be-t distribution curve B elimination curve 0t

  42. 4. Parameters of pharmacokinetics and their meanings (1)AUC (2)Bioavailability(F); (2)Apparent volume of distribution(Vd); (3)Half-life time(t½).

  43. (1)Area under the conentration-time curve (AUC，曲线下面积) AUC代表进入体循环的药物的相对量, 可由梯形法则求得, 单位为 g/ml·min 或 mg/L·h. Cmax tmax

  44. (2)Bioavailability(生物利用度, F) Fraction of absorption(吸收分数) F = A / D ×100% F = AUC(po)/AUC(iv)×100% F = AUC(供试药)/AUC(对照药)×100% Affected factors: Rate of absorption First pass elimination(p.o.)

  45. Routes of administration, bioavailability,and general characteristics.

  46. 某药剂量相等的三种制剂的生物利用度比较 F(AUC)相等, 但Tmax与Cmax不等

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