Transcript Vmax - Farmasi Unand

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
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•
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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 firstorder 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
Cause
Saturable gastric or GI
decomposition
Drug
Penicillin G, OMZ,
saquinavir
Saturable transpor in gut Riboflavin, gebapentin,
wall
L-dopa, baclofen
Intestinal metabolism
Salicylamide,
propranolol
Low solubility but high
dose
Chlorotiazide,
griseofulvin, danazol
Distribution
Cause
Drug
Saturable transport into/
out of tissues
Saturable plasma
protein binding
Cellular uptake
MTX
Tissue binding
IMI
CSF transport
Benzylpenicillins
Phenylbutazone,
lidocaine, salicylic acid
Methicillin
Metabolism
Cause
Saturable metabolism
Drug
Enzymes induction
Phenytoin, salicylic acid,
theophyllin, valproic acid
Carbamazepine
Enzymes limitations
PCT, alcohol
Altered hepatic blood
flow
Metabolite inhibition
Propranolol, verapamil
Diazepam
Renal Excretion
Cause
Drug
Active secretion
Mezlocillin, paminohippuric 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