Pharmacokinetics

1. Pharmacokinetics • PK process in the body • Kinetic processes 张翔南 浙江大学药学院 xiangnan_zhang@zju.edu.cn 医学院科研楼B404

2. Part APharmacokinetic Processes • 1 Overview • 2 Transport of Drug in the Body • 3 Pharmacokinetic Processes of the Drug in the Body

3. 1.Overview

4. ADME of the drug in human body

5. Part APharmacokinetic Processes • 2. Transport of Drug in the Body • 2.1 Transmembrane Transport of • Drugs • (1) Passive Transport • Simple diffusion（简单扩散） • Filtration（滤过）

6. Part APharmacokinetic Processes • Characteristics of Passive Transport • not involving specific carriers • Energy-independent • no saturability • no competition with other drugs • Concentration gradient (down-hill)

7. Part APharmacokinetic Processes • (2) Active Transport • Characteristics of active transport • Involving specific carrier • Energy-dependent • Saturability • Competition at same carrier • Moving against concentration gradient (up-hill)

8. Part APharmacokinetic Processes • (3) Others • Filtration through pores（膜孔滤过） • Facilitated diffusion（易化扩散） • Endocytosis（内吞） • Pinocytosis（胞饮） • Ion-pair transport（离子对转运）

9. Three types of functional membrane proteins.

10. Transporters of drugs in PK processes

11. Part APharmacokinetic Processes • Simple diffusion

12. Part APharmacokinetic Processes • 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 • The pKais that pH at which the concentrations of the ionized and un-ionized forms are equal.

13. Part APharmacokinetic Processes • 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+] )

14. Part APharmacokinetic Processes Simple diffusion un-ionized form lipid-soluble pKa pH Weak acids And / or And / or And / or Weak bases And / or

17. pH < pKa:HA and BH+ are predominant pH > pKa:A－ and B are predominant

18. Part APharmacokinetic Processes • Implications • Absorption • Distribution • Excretion

20. Part APharmacokinetic Processes • 2.2 Free and Bound Forms • Plasma protein binding • Tissue / organ affinity

21. Part APharmacokinetic Processes • 3. Fate of the drug in the body • Absorption • Distribution • Biotransformation • ( metabolism) • Excretion • － ADME

22. Part APharmacokinetic Processes • 3.1 Absorption • Absorption is the transfer of a drug from its site of administration to the blood stream. • Gastrointestinal tract • Parenteral injection im. sc. • Inhalation • Transdermal

23. Part APharmacokinetic Processes • (1) Gastrointestinal tract • Route: • Oral • Sublingual • Rectal

24. Part APharmacokinetic Processes • 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

25. Part APharmacokinetic Processes • First-pass elimination • When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased.

26. First-pass elimination

27. Part APharmacokinetic Processes • (2) Parenteral injection • intramuscular injection ( im ) • subcutaneous injection ( sc ) • Determinants • Local blood flow • Solubility of the drug

28. Part APharmacokinetic Processes • (3) Others • Inhalation • Intranasal • Transdermal • Topical

29. Part APharmacokinetic Processes • 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.

30. Body fluid volume: Sites of drug distribution

31. Part APharmacokinetic Processes • (1) Binding of drug to plasma proteins • Bound drug: • Inactive temporily • can not distribution • reversible (storage form) • percentage of binding • competitively displacement

32. Part APharmacokinetic Processes • competitively displacement • Class I drugs: Dose less than available binding sites. Most drug molecules are bound to the proteins and free drug concentration is low. • Class II drugs: Dose greater than available binding sites. Most proteins contain a bound drug and free drug concentration is significant. • Class I + Class II drugs: Displacement of Class I drug occures when a Class II drug is administered simultaneously.

34. Part APharmacokinetic Processes (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

35. Blood-brain barrier (BBB) Able to pass throughUnable to pass through Small moleculesLarge molecules Lipid-solubleWater-soluble Transporter-mediation

36. Structure of liver capillary and brain capillary

37. Part APharmacokinetic Processes Amount of drug passing through blood-brain barrier Percentage of drug in c.s.f. Increases when Inflammation Larger doses used

38. BBB permeability increases in inflammation

39. Placental barrier: More permeable

40. Part APharmacokinetic Processes • 3.3 Biotransformation (drug metabolism) • (1) Biotransformation sites • Liver:most of the drugs • Other organs/tissues:intestine, kidney, lung, plasma, etc.

41. Part APharmacokinetic Processes • (2) Phases of biotransformation • Phase I: Oxidation reduction hydrolysis • most drugs are inactivated • few (prodrugs) are activated • Phase II: Conjugation • inactivated • Metabolites: more water-soluble • easier to excrete

42. Part APharmacokinetic Processes • Drugs or other substances • Phase I • inactivated（few: activated） • Phase II • inactivated • Excretion

43. Part APharmacokinetic Processes • (3) Enzymes in biotransformation • Enzymes in Phase I: • cytochrome-P450 • many other enzymes • Enzymes in Phase II: • acetylase • glucuronosyltransferase • etc.

44. Superfamily of cytochrome-P450 CYP3A4 （cytochrome / family / subfamily / member）

45. Part APharmacokinetic Processes • (4) Hepatic enzymes of drug metabolism • hepatic microsomal mixed function oxidase system （肝药酶） • Extraction > 0.7: hepatic blood flow dependent • － nitroglucerin, propranolol, … • Extraction < 0.3: hepatic enzyme dependent • － diazepam, phenobarbital, …

46. Part APharmacokinetic Processes • Induction of hepatic enzymes by drugs • example: • phenobarbital－steroids, warfarin • Inhibition of hepatic enzymes by drugs • example: • cimetidine－diazepam

47. 肝药酶诱导剂对双香豆素血浓度及凝血作用的影响肝药酶诱导剂对双香豆素血浓度及凝血作用的影响

48. Part APharmacokinetic Processes • 3.4 Excretion • (1) Excretion routes • Kidney • Bile • Lung • GI tract • Milk • Secretion glands

49. Part APharmacokinetic Processes • (2) Renal excretion • Glomerular filtrattion • renal blood flow • Active tubule secretion • specific carriers / competition • Passive tubule reabsorption • urine pH, urine flow

50. Renal excretion Glumerular fitration Active secretion Passive reabsorption