Overview of Drug Transport and Permeation in Pharmacokinetics

1. Chapter 1Pharmacokinetics药物代谢动力学 • PK process in the body • Kinetic processes

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

3. Overview

4. C. carriers (transporters) (into or out of cells) D. endocytosis exocytosis A. aqueous channels in the intercellular junctions B. lipid cell membranes Mechanisms of drug permeation

5. Part APharmacokinetic Processes • 2. Transport of Drug in the Body • 2.1 Transmembrane Transport of Drugs • (1) Non-carrier transport • Simple diffusion（简单扩散/单纯扩散） • Filtration（滤过）

6. Part APharmacokinetic Processes Characteristics of simple diffusion Not involving specific carriers Energy-independent No saturability No competition with other drugs Concentration gradient (down-hill)

7. Part APharmacokinetic Processes • (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)

8. Part APharmacokinetic Processes • 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) Membrane moving transport（膜动转运） • Endocytosis/exocytosis（入胞/出胞）

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

10. 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 • ThepKais the pH at which the concentrations of the ionized and un-ionized forms are equal.

11. 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+] )

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

13. Part APharmacokinetic Processes • Implications • Absorption: Stomach/intestine • Distribution: Plasma/intracellular • Excretion: Urine pH/weak acid or base

14. Weak acid

15. Weak base Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood

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

17. Models of transmembrane transport across the lipid bilayer

18. Transporter superfamily（转运体超家族） • 根据不断增加的转运体成员，人类基因命名委员会对转运体作了标准化命名，分为两大类： • ATP-结合盒转运体（ATP-binding cassette [ABC] transporters）— mediating active transport • 12次跨膜结构 （P-gp、MRP4、MRP5） • 17次跨膜结构 （MRP1、MRP2、MRP3、MRP6） • 6次跨膜结构 （BCRP, 组成二聚体发挥作用） • 溶质载体转运体（solute carrier [SLC] transporters） — mediating facilitated diffusion • 有机阴离子转运体（organic anion transporter, OAT）家族 • 有机阳离子转运体（organic cation transporter, OCT）家族 • 多肽转运体（peptide transporter, PEPT） • 核苷转运体（nucleoside transporter, NT）

19. Primary active transport (P-glycoprotein, multidrug resistance protein [MRP] ) Secondary active transport + facilitated diffusion (organic anion / caion transporters)

20. Transporters of drugs in PK processes

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

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

23. 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 - i.m., s.c. • Inhalation • Transdermal

24. Part APharmacokinetic Processes • (1) Gastrointestinal tract • Route: • Oral • Sublingual • Rectal • Absorption sites: • Oral • Gastric • Intestinal • Rectal

25. 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

26. Part APharmacokinetic Processes • First-pass elimination（首过消除） • 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 or intestinal mucosa, the amount of unchanged drug that gains access to the systemic circulation is decreased.

27. Part APharmacokinetic Processes • (2) Parenteral injection • intramuscular injection ( i.m. ) • subcutaneous injection ( s.c. ) • Determinants • Local blood flow • Solubility of the drug

28. Part APharmacokinetic Processes • (3) Others • Inhalation • Transdermal • Intranasal • 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. • Blood flow-dependent phase of distribution • Selective distribution • Tissue-plasma balance: importance of measuring plasma concentration

30. Body fluid volume: Sites of drug distribution

31. Part APharmacokinetic Processes • (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

32. Part APharmacokinetic Processes • Competitive 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 occurs when a Class II drug is administered simultaneously.

33. Example: Class I:Tolbutamide (甲苯磺丁脲) Class II:Sulfonamide (磺胺类药物) competitive displacement

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

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

38. Part APharmacokinetic Processes • 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.

39. Part APharmacokinetic Processes • (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

40. Part APharmacokinetic Processes

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

42. Superfamily of cytochrome-P450 CYP2A6（cytochrome-P450 / family / subfamily / member）

43. Part APharmacokinetic Processes • (4) Properties of drug metabolism enzymes • a. Lower selectivity to substrates • b. Larger individual variability • c. Induction and inhibition by environmental determinants (including drugs)

44. Rapid acetylation Slow acetylation Individual variability of isoniazid metabolism

45. Part APharmacokinetic Processes • Induction of hepatic enzymes by drugs • example: • phenytoin－steroids, nifedipine • Inhibition of hepatic enzymes by drugs • example: • verapamil－diazepam

46. 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

47. Part APharmacokinetic Processes • 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

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. Part APharmacokinetic Processes • (3) Bile excretion • Carrier-mediated active • transport • Hepato-enteral circulation