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Transcript of NON LINEAR PHARMACOKINETICS Dr. Muslim Suardi, MSi., Apt. Faculty of Pharmacy University of Andalas...
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NON LINEAR PHARMACOKINETICS
Dr. Muslim Suardi, MSi., Apt. Faculty of PharmacyUniversity of Andalas
2013
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NON LINEAR PHARMACOKINETICS
“Dose-dependent pharmacokinetics”
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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”
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Causes
Saturation of enzymes in process of drug ADME
Pathologic alteration in drug ADME
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Remember!
Saturation of enzymes
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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
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Process Saturated
Absorption
Distribution
Metabolism
Excretion
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Process usually saturated
Metabolism
Active tubular secretion
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Caution!
Drug concentration in the blood can increased rapidly once an elimination
process is saturated !!!!!!!!
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Limited Metabolism
• Glycine conjugation of salicylate• Sulfate conjugation of salicylamide• Acetylation of p-aminobenzoic acid • Elimination of phenytoin
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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
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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
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Examples of Drugs
Non linear kinetics in: • GI absorption • Distribution • Metabolism• Renal Excretion • Biliary Excretion
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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
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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
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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
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Renal Excretion
Cause Drug
Active secretion Mezlocillin, p-aminohippuric acid
Tubular reabsorption Riboflavin, ascorbic acid, cephapirin
Change in urine pH Salicylic acid, dextroamphetamine
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Biliary Excretion
Cause Drug
Biliary secretion Iodipamide, sulfobromophthalein sodium
Enterohepatic recycling Cimetidine, isotretinoin
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Michaelis-Menten Kinetics
• The elimination of drug by a saturable enzymatic process
• Elimination Rate =
dCp/dt= (Vmax.Cp)/(KM+Cp)
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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
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dCp/dt= (Vmax.Cp)/(KM+Cp)
If Cp >>>>> KM,
thus • Elimination of drugs becomes a zero
process:
• dCp/dt = (Vmax.Cp)/(Cp)= Vmax
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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
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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