NON LINEAR PHARMACOKINETICS Dr. Muslim Suardi, MSi., Apt. Faculty of Pharmacy University of Andalas 2013

NON LINEAR PHARMACOKINETICS “Dose-dependent pharmacokinetics”

NON LINEAR PHARMACOKINETICS Some drugs Increasing doses or multiple doses can cause: “Deviations from linear pharmacokinetic profile observed with single low doses of the same drug”

Causes Saturation of enzymes in process of drug ADME Pathologic alteration in drug ADME

Remember! Saturation of enzymes

Examples Aminoglycoside may cause renal nephrotoxicity, thereby altering renal drug excretion Obstruction of the bile duct to the formation of gallstone will alter biliary drug excretion

Process Saturated Absorption Distribution Metabolism Excretion

Process usually saturated Metabolism Active tubular secretion

Caution! Drug concentration in the blood can increased rapidly once an elimination process is saturated !!!!!!!!

Limited Metabolism Glycine conjugation of salicylate Sulfate conjugation of salicylamide Acetylation of p-aminobenzoic acid Elimination of phenytoin

Characteristics of Saturation Kinetics Drug Elimination of drug does not follow first- order kinetic T1/2 el changes as dose is increased AUC is not proportional to the amount of bio-available drug

Characteristics of Saturation Kinetics Drug Saturation of capacity-limited processes may be affected by other drugs that require the same enzyme/carrier system The composition of the metabolites of a drug may be affected by a change in the dose

Examples of Drugs Non linear kinetics in: GI absorption Distribution Metabolism Renal Excretion Biliary Excretion

GI absorption Saturable gastric or GI decomposition Penicillin G, OMZ, saquinavir Saturable transpor in gut wall Riboflavin, gebapentin, L-dopa, baclofen Intestinal metabolismSalicylamide, propranolol Low solubility but high dose Chlorotiazide, griseofulvin, danazol CauseDrug

Distribution Saturable transport into/ out of tissues MTX Saturable plasma protein binding Phenylbutazone, lidocaine, salicylic acid Cellular uptakeMethicillin Tissue bindingIMI CSF transportBenzylpenicillins CauseDrug

Metabolism CauseDrug Saturable metabolismPhenytoin, salicylic acid, theophyllin, valproic acid Enzymes inductionCarbamazepine Enzymes limitationsPCT, alcohol Altered hepatic blood flow Propranolol, verapamil Metabolite inhibitionDiazepam

Renal Excretion CauseDrug Active secretionMezlocillin, p- aminohippuric acid Tubular reabsorptionRiboflavin, ascorbic acid, cephapirin Change in urine pHSalicylic acid, dextroamphetamine

Biliary Excretion CauseDrug Biliary secretionIodipamide, sulfobromophthalein sodium Enterohepatic recyclingCimetidine, isotretinoin

Michaelis-Menten Kinetics The elimination of drug by a saturable enzymatic process Elimination Rate = dCp/dt= (Vmax.Cp)/(KM+Cp)

Michaelis-Menten Kinetics dCp/dt= (Vmax.Cp)/(KM+Cp) Vmax= Maximum elimination rate KM= Michaelis constant The values for Vmax and KM are dependent on the nature of the drug in the plasma

dCp/dt= (Vmax.Cp)/(KM+Cp) If Cp >>>>> KM, thus Elimination of drugs becomes a zero process: dCp/dt= (Vmax.Cp)/(Cp) = Vmax

Determination of Vmax & KM When an experiment is performed with solutions of various concentration of the drug C, a series of reaction rates |(v) may be measured for each concentration. Special plots may be then be used to determine Vmax & KM

Determination of Vmax & KM v = (Vmax.C)/(KM + C) 1/v = (KM/Vmax). 1/C + 1/Vmax Equation is a linear when 1/v is ploted against 1/C. Intercept for the line is -1/Km & the slope is Km/Vmax