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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