Part 2 Pharmacokinetics 药物代谢动力学

1. Part 2Pharmacokinetics药物代谢动力学

2. Kinetics Models Parameters

3. C.carriers (transporters) (into or out of cells) D.endocytosis exocytosis A.aqueous channels in the intercellular junctions B.lipid cell membranes • 2. Transport of Drug in the Body Mechanisms of drug permeation across cell membrane

4. 2.1 Transmembrane Transport of Drugs • (1) Non-carrier Transport • Simple diffusion（简单扩散/单纯扩散） • Filtration（滤过）

5. (2) Carrier-mediated Transport • a. Active transport • Characteristics of active transport • Involving specific carrier (transporter) • Energy-dependent • Saturability • Competition at same carrier • Moving against concentration gradient (up-hill)

6. b. Facilitated diffusion（易化扩散） • (transporter-mediated diffusion) • Involving specific carriers (transporter) • Energy-independent • Saturability • Competition with other drugs • Concentration gradient (down-hill) • (3) Endocytosis/exocytosis（入胞/出胞）

7. Another classification • Passive transport • Simple diffusion（简单扩散/单纯扩散） • Filtration（滤过） • Facilitated diffusion（易化扩散） • Active transport • Active transport (主动转运) • Pinocytosis/exocytosis（入胞/出胞）

8. Most drugs are weak acids or bases. Their diffusion passing through cell membrane depends the lipid-soluble state (un-ionized form) • A. Simple diffusion

9. Determinants of simple diffusion • For most drugs of small molecules (usually are weak acids or weak bases): • Lipid-soluble or un-ionized forms • pKa of the drug andpHof the body fluid • ThepKais the pH at which the concentrations of the ionized and un-ionized forms are equal.

10. Henderson-Hasselbalch equation • Weak acid drugs: • pH - pKa = log ( [A-] / [HA] ) • pKa - pH = log ( [HA] / [A-] ) • Weak base drugs: • pKa - pH = log ( [BH+] / [B] ) • pH - pKa = log ( [B] / [BH+] )

11. Simple diffusion un-ionized form lipid-soluble pKa pH Weak acids And / or And / or And / or Weak bases And / or

12. B. Carrier (transporter)-mediated transport Three types of functional membrane proteins.

13. Models of transmembrane transport across the lipid bilayer

14. 2.2 Free and Bound Forms • Plasma protein binding • Tissue / organ affinity

15. 3. Fate of the drug in the body • Absorption • Distribution • Metabolism • (Biotransformation) • Excretion • － ADME ADME

16. 3.1 Absorption • Absorption is the transfer of a drug from its site of administration to the blood stream. • Gastrointestinal tract • Parenteral injection - i.m., s.c. • Inhalation • Transdermal

17. (1) Gastrointestinal tract • Route: • Oral • Sublingual • Rectal • Absorption sites: • Oral • Gastric • Intestinal • Rectal

18. Factors influencing absorption: • blood flow to the absorption site • total surface area available for absorption • contact time at the absorption surface • physic-chemical properties of the drug • first-pass elimination

19. (2) Parenteral injection • intramuscular injection ( i.m. ) • subcutaneous injection ( s.c. ) • Determinants • Local blood flow; Solubility of the drug • (3) Others • Inhalation; Intranasal; • Transdermal; Topical

20. 3.2 Distribution • Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and / or the cells of the tissues. • Blood flow-dependent phase of distribution • Selective distribution • Tissue-plasma balance:importance of measuring plasma concentration

21. (1) Binding of drug to plasma proteins • Bound drug: • can not distribute / inactive temporally • reversible (storage form) / percentage of binding • plasma protein capacity • competitive displacement

22. (2) Physic-chemical properties of the drug (3) Blood flow and re-distribution (4) Affinity to organs or tissues (5) Barriers Blood-brain barrier (BBB) Placental barrier Blood-eye barrier

23. Blood-brain barrier (BBB) Able to pass throughUnable to pass through Small moleculesLarge molecules Lipid-solubleWater-soluble Transporter-mediation Amount of drug passing through BBB Increases when inflammation or larger doses used

24. Placental barrier: More permeable Drugs for pregnant women: A, B – relatively safe C - caution D,X - toxic

25. 3.3 Metabolism (biotransformation) • Drug metabolism is the process transforming lipophilic drug into more hydrophilic metabolites, which is essential for the elimination of these compounds from the body and termination of their biological activity. • (1) Metabolism sites • Liver:for most of the drugs • Other organs/tissues:intestine, kidney, lung, plasma, etc.

26. (2) Phases of metabolism • Phase I: Oxidation, reduction, hydrolysis • most drugs are inactivated • few (prodrugs) is activated • Phase II: Conjugation • inactivated • Metabolites: more water-soluble easier to excrete

28. (3) Enzymes in drug metabolism • Enzymes in Phase I: • cytochrome-P450, such as CYP2A6, CYP3A4 • many other enzymes • Enzymes in Phase II: • acetylase • glucuronosyltransferase • etc.

29. Induction of hepatic enzymes by drugs • example: • phenytoin－steroids, nifedipine • Inhibition of hepatic enzymes by drugs • example: • verapamil－diazepam

30. 3.4 Excretion • Removal of a drug from the body via a number of routes. • Elimination of drugs from the body • Action on excretory organs

31. 3.4 Excretion • (1) Excretion routes • Kidney -renal excretion • Bile (hepato-enteral circulation) • Lung • GI tract • Milk • Secretion glands

32. 3.5 Elimination and Accumulation • Elimination（消除） • Metabolism • Excretion • Distribution (stored in fat, hair, etc) • Accumulation（蓄积） • Dosing rate > elimination rate

33. Kinetic Processes Kinetics Models Parameters • 1. Drug concentration-time curve (C-T curve) • 2. Kinetic rate processes • 3. Pharmacokinetic models • 4. Pharmacokinetic parameters and their implications

34. Kinetic Processes • 1. Drug concentration-time curve(C-T curve) • Maximal (peak) concentration:CmaxorCp • Time to maximal concentration (Peak time ) : • Tmaxor Tp • Area under the curve:AUC • Multiple dosing (steady state): • Css max, Css min, Css

35. ← ← ← ← C Cmax Cp i.v. i.m. s.c. Oral ↑ ↑ ↑ t Tmax, Tp

36. ←Cmax C AUC ↑ Tmax t Tmax, Cmax and AUC

37. C-T curve after multiple dosing(same dose and interval) 在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓度，用Css表示

38. 2. Kinetic rate processes • dC / dt ＝ －KCn

39. 2.1 Zero order kinetics • n ＝ 0 • dC / dt ＝ －K • Ct＝ C0－K t • C0－Ct＝ K t • when Ct＝1/2 C0,t = t1/2 • then, 0.5 C0＝K t1/2 • t1/2＝0.5 C0 / K

40. Zero order kinetics • A. same amounts of drug are • eliminated per unit time • B. t1/2 is not a constant • C. C-T curve is linear • D. no Css theoretically

41. Kinetic properties of C-T curves after single bolus injection of drug

42. 2.2 First order kinetics • n ＝ 1 • dC / dt ＝ －KC • Ct ＝ C0e－Kt • lnCt ＝ lnC0－Kt • Kt＝lnC0－lnCt＝ln(C0 / Ct) • when Ct＝1/2C0，t＝t1/2，then • t1/2＝ln2/K＝0.693/K

43. First order kinetics • A. eliminated at same rate per unit time • B.t1/2 is a constant • C. logC-T curve is linear • D. steady state (Css) after 4-5 t1/2

44. Kinetic properties of C-T curves after single bolus injection of drug

45. 2.3 Non-linear kinetics • Higher concentration (or larger dose): • zero order kinetics • Lower concentration (or smaller dose): • first order kinetics • Because of limits in elimination capacity • Examples:aspirin, phenytoin, ethanol • Confirmation:different t1/2 when given different doses

46. Michaelis-Menten kinetics • dC / dt = Vmax  C / (Km + C) • if Km >> C • dC / dt = Vmax  C / Km • Vmax / Km = Ke － First order • ifC >> Km • dC / dt = Vmax  C / C • dC / dt = -Vmax－ Zero order

47. Kinetic properties of C-T curves after single bolus injection of drug

48. Kinetic properties of C-T curves after single dose of aspirin

49. One-compartment model • 3. Pharmacokinetic models iv logC t

50. 3.2 Two-compartment model 1 2 2, 3 First, enter the central compartment Then, distributed to peripheral compartment, and eliminated