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Understanding Drug Transport and Metabolism: A Comprehensive Overview

This detailed guide explores the pharmacokinetics of drug transport, including mechanisms of permeation, transmembrane transport, carrier-mediated transport, and endocytosis/exocytosis. It covers the role of carriers (transporters) in moving drugs across cell membranes and the importance of factors like lipid solubility and ionization state in drug diffusion. Additionally, it delves into the fate of drugs in the body, discussing absorption, distribution, metabolism (biotransformation), and excretion processes. The complex interplay of absorption sites, distribution phases, plasma protein binding, and tissue affinity is elucidated, along with the significance of drug metabolism in transforming compounds for elimination. Key barriers like the blood-brain barrier and placental barrier are highlighted, shedding light on their impact on drug passage. Relevant terminology and concepts are explained in an accessible manner to enhance understanding of drug kinetics.

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Understanding Drug Transport and Metabolism: A Comprehensive Overview

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  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

  27. (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.

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

  29. 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

  30. 3.4 Excretion • (1) Excretion routes • Kidney -renal excretion • Bile (hepato-enteral circulation) • Lung • GI tract • Milk • Secretion glands

  31. 3.5 Elimination and Accumulation • Elimination(消除) • Metabolism • Excretion • Distribution (stored in fat, hair, etc) • Accumulation(蓄积) • Dosing rate > elimination rate

  32. 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

  33. 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

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

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

  36. 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

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

  38. 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

  39. 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

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

  41. 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

  42. 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

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

  44. 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

  45. 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

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

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

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

  49. 3.2 Two-compartment model 1 2 2, 3 First, enter the central compartment Then, distributed to peripheral compartment, and eliminated

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