Nonlinear_Pharmacokinetics_Reconstructed.pptx

its about non linear pharmacokinetic

1. Nonlinear Pharmacokinetics Detailed Notes (Colorful PPT)

2. Contents Introduction Linear & Nonlinear Pharmacokinetics Detection of Non-linearity Causes of Nonlinearity Michaelis–Menten Equation Estimation of Km and Vmax

3. Linear Pharmacokinetics At therapeutic doses, change in drug concentration is proportional to dose. Follows first-order kinetics; semilog plots superimpose for different doses. Pharmacokinetic parameters (F, Ka, KE, Vd, Clr, Clh) remain unaffected. Pharmacokinetics is dose independent.

4. Nonlinear Pharmacokinetics Rate processes depend on carrier/enzyme with limited capacity. First-order → mixed-order (zero + first) at high dose. Pharmacokinetics become dose-dependent.

5. Examples of Saturable Processes Glycine conjugation of salicylate Sulphate conjugation of salicylamide Acetylation of p-aminobenzoic acid Elimination of phenytoin

6. Characteristics of Saturation Kinetics Elimination kinetics are nonlinear. t½ changes with dose (usually ↑). AUC not proportional to dose. Affected by competition for enzymes/carriers. Metabolite ratio may change.

7. Detection of Non-Linearity 1) Measure steady-state concentrations at different doses. 2) Measure PK parameters (F, t½, Cl) at different doses → changes indicate nonlinearity.

8. Causes of Non-Linearity - Absorption Solubility/dissolution limited absorption (Griseofulvin). Carrier-mediated transport saturation (Ascorbic acid). Presystemic metabolism saturation (Propranolol). F, Ka, Cmax, AUC ↓ (1,2) or ↑ (3).

9. Causes of Non-Linearity - Distribution Plasma protein binding saturation (Phenylbutazone). Tissue binding saturation. Results: ↑ plasma concentration, ↑ Vd (only with protein binding saturation), ↑ clearance.

10. Causes of Non-Linearity - Metabolism Capacity-limited metabolism (Phenytoin, Alcohol). Enzyme induction → ↓ Css (Carbamazepine). Autoinduction possible. Saturation: ↓ Clh → ↑ Css.

11. Causes of Non-Linearity - Excretion Saturable tubular secretion (Penicillin G). Saturable tubular reabsorption (Vitamins, Glucose). Carrier saturation: ↓ Cl (I), ↑ Cl (II). Biliary excretion saturation: Tetracycline, Indomethacin.

12. Michaelis-Menten Kinetics E + D ⇌ ED → E + M Rate: -dC/dt = (Vmax·C)/(Km + C)

13. Michaelis-Menten Special Cases Km = C → rate = Vmax/2 Km >> C → first-order kinetics Km << C → zero-order kinetics (rate = Vmax)

14. Estimation of Km and Vmax Css vs DR gives hockey-stick curve. Methods: Lineweaver-Burke, Direct Linear Plot, Graphical Method.

15. Phenytoin Nonlinear PK Km ~ 4 mg/L (within/below therapeutic range). Therapeutic range: 10–20 mg/L → risk of accumulation. t½ may increase > 24 h. Doses near Vmax → risk of overdose.