NON LINEAR PHARMACOKINETICS

Dr. Muslim Suardi, MSi., Apt. Faculty of PharmacyUniversity 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 metabolism Salicylamide, propranolol

Low solubility but high dose

Chlorotiazide, griseofulvin, danazol

Cause Drug

Distribution

Saturable transport into/ out of tissues

MTX

Saturable plasma protein binding

Phenylbutazone, lidocaine, salicylic acid

Cellular uptake Methicillin

Tissue binding IMI

CSF transport Benzylpenicillins

Cause Drug

MetabolismCause Drug

Saturable metabolism Phenytoin, salicylic acid, theophyllin, valproic acid

Enzymes induction Carbamazepine

Enzymes limitations PCT, alcohol

Altered hepatic blood flow

Propranolol, verapamil

Metabolite inhibition Diazepam

Renal Excretion

Cause Drug

Active secretion Mezlocillin, p-aminohippuric acid

Tubular reabsorption Riboflavin, ascorbic acid, cephapirin

Change in urine pH Salicylic acid, dextroamphetamine

Biliary Excretion

Cause Drug

Biliary secretion Iodipamide, sulfobromophthalein sodium

Enterohepatic recycling Cimetidine, 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