2章 药物代谢动力学 - ahmu.edu.cn

1 2 . Pharmacokinetics Department of pharmacology, Anhui medical university . (disposition) . (absorption). (distribution). (metabolism). (excretion).. Department of pharmacology, Anhui medical university Pharmacokinetics Drug Administration Absorption Drug in Drug Drug Tissues of Concentration in Metabolism Distribution Systemic or Excreted Circulation Distribution Elimination Drug Concentration at Site of Action Pharmacodynamics Pharmacologic Effect Clinical Response Toxicity Efficacy Department of pharmacology, Anhui medical university . Drug transport Department of pharmacology, Anhui medical university .. Department of pharmacology, Anhui medical university .. Department of pharmacology, Anhui medical university 1.

2 (Simple diffusion, Passive diffusion).. lipid solubility .. (pKa) . Department of pharmacology, Anhui medical university (Acidic drug): HA ' H+ + A . (Basic drug): BH+ ' H+ + B ( ). (ion trapping) .. H+ H+. A- B BH+. HA. HA A- B BH+. H+ H+. Department of pharmacology, Anhui medical university pH pKa . [ H+ ] [ A ]. Ka =. [HA]. [ A ]. pKa = pH - log [HA]. [ A ]. 10 pH-pKa =. [HA]. pKa-pH. Department of pharmacology, Anhui medical university 2. Filtration .. 4 8 (=10 10m) . >100.. Department of pharmacology, Anhui medical university 3 (Active transport).. 5- .. Department of pharmacology, Anhui medical university 4. (Facilitated diffusion; Carrier-mediated diffusion).. Glucose, Iron, 5-fluorouracil, calcium, lead . Department of pharmacology, Anhui medical university ADME.

3 Absorption Distribution Metabolism Excretion Department of pharmacology, Anhui medical university 1. (Absorption): . (1) (Oral ingestion).. pH 5-8 . Department of pharmacology, Anhui medical university (First pass eliminaiton).. Department of pharmacology, Anhui medical university 2 . (Intramuscular and subcutaneous injection).. Department of pharmacology, Anhui medical university 3 (Inhalation).. 100-200m2. ( 80 m2. 4 (Transdermal).. 5 . Department of pharmacology, Anhui medical university 2 (Distribution).. Receptor Free bound Free drug . Bound Tissue Drug Free bound Metabolites Excretion Department of pharmacology, Anhui medical university Factors modulating drug distribution . pH .. Department of pharmacology, Anhui medical university (Plasma protein binding).)

4 KD Reversible equilibrium D P DP. Saturable [DP] [D] DP: Non-permeable [PT] KD +[D] Nonspecific & competitive Plasma proteins Albumin: Weak acids alpha-acid glycoprotein: Weak bases Effects of plasma protein binding Free fraction: active, excreted, metabolized the more binding, the less active drug the more binding, the less excreted and metabolized: longer half-life . Department of pharmacology, Anhui medical university . (Blood-brain barrier, BBB).. N .. Department of pharmacology, Anhui medical university Placental barrier .. Department of pharmacology, Anhui medical university 3. (metabolism, , biotransformation ).. Phase I Phase II.. (-OH -CH3 - I . NH2 -SH) .. Department of pharmacology, Anhui medical university (Oxidation).

5 P450 . CYP1B1 CYP2A6. CYP1A1/2 CYP2B6. CYP2C8. Non-CYP. enzymes CYP2C9. CYP2C19. CYP3A4/5/7 CYP 2D6. CYP2E1. Department of pharmacology, Anhui medical university . z (Induction) .. ( ). ( ). z (Inhibition) .. Department of pharmacology, Anhui medical university 4. Excretion).. Glomerular Fitration Rate (GFR): 125ml/min Urine 1ml/min Plasma flow 650ml/min Acid Base 99% of H20 +. Lipid soluble drugs Filtration Active secretion Reabsorption Department of pharmacology, Anhui medical university . Liver (Biliary excretion) Bile duct &. Gut Portal vein (Enterohepatic recycling). Feces excretion Department of pharmacology, Anhui medical university - . Time course of drug concentration Department of pharmacology, Anhui medical university.

6 10. Plasma aspirin concentration (mg/L). 8. Cmax 6 . 4. 2. Tmax 0. 0 20 40 60 80 100 120. Time (min). Department of pharmacology, Anhui medical university Cmax . y . Plasma concentration y . AUC . ng h/mL.. AUC. Area under curve hrs Tmax . Department of pharmacology, Anhui medical university (Constant repeated administration of drugs). (Steady-state concentration). : MTC>Css>MEC. 4-5 half-life Css-max < MTC. Css-min > MEC. Department of pharmacology, Anhui medical university . 94% 97%. Department of pharmacology, Anhui medical university . Elimination Kinetics Department of pharmacology, Anhui medical university . k . (Rate constant for elimination). dC/dt = - kCn .. (First order elimination kinetics ). n=1 dC/dt = - kC.

7 (Zero order elimination kinetics). n=0 dC/dt = k . Department of pharmacology, Anhui medical university . Important Parameters in Pharmacokinetics Department of pharmacology, Anhui medical university Half-life, T1/2 .. : : t1/2 = t1/2 = C0/k .. Slope( ).. = - t1/2 t1/2 t1/2 t1/2 t1/2. h h . Department of pharmacology, Anhui medical university Clearance CL .. L/h ml/min CL=CL CL CL . CL = A/AUC. Department of pharmacology, Anhui medical university Volume of distribution .. Vd A C.. Department of pharmacology, Anhui medical university Vd . z . Digoxin ng/ml Vd = 645 L.. 30 . z Vd=D/C. Department of pharmacology, Anhui medical university Bioavailability .. z . AUC . F= 100%. AUC . z . AUC . F = (AUC AUC ) 100%. Department of pharmacology, Anhui medical university