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NON LINEAR

PHARMACOKINETICS


Also known as:
Dose-dependent Pharmacokinetics
Saturable kinetics
Capacity-limited pharmacokinetics

There is a pathologic alteration in drug
absorption, distribution, and
elimination
EXAMPLE:
a.) aminoglycosides may
cause renal nephrotoxicity,
thereby altering renal drug
excretion
b.) gallstone obstruction of the
bile duct will alter biliary drug
excretion
EXAMPLES OF DRUGS SHOWING NONLINEAR KINETICS
Cause Drug
GI Absorption
Saturable transport in gut wall Riboflavin, L-dopa
Intestinal metabolism Propranolol
Distribution
Saturable plasma protein
binding
Lidocaine, ceftriaxone, phenytoin,
warfarin
Saturable transport into or out
of tissues
Methotrexate
Renal Elimination
Tubular reabsorption Riboflavin, ascorbic acid
Change in urine pH Salicylic acid, dextroamphetamine
Metabolism
Saturable metabolism Phenytoin, theophylline
Cofactor or enzyme limitation Acetaminophen, alcohol
Enzyme induction Carbamazepine
Altered hepatic blood flow Propranolol, verapamil
Metabolite inhibition Diazepam
Biliary Excretion
Enterohepatic recycling Cimetidine, isotretinoin

A number of drugs demonstrate
saturation or capacity-limited
metabolism.
EXAMPLE of saturable metabolic
processes:
1.) glycine conjugation of salicylate
2.) sulfate conjugation of salicylamide
3.) acetylation of p-aminobenzoic acid,
4.) elimination of phenytoin

CHARACTERISTICS OF DRUGS THAT DEMONSTRATE
SATURATION KINETICS
1.) Elimination of drug are nonlinear.
2.) The elimination half-life changes as dose is
increased.
3.) The area under the curve (AUC) is not
proportional to the amount of
bioavailable drug.
4.) Competition effect
5.) The composition and/or ratio of the
metabolites of a drug may be
affected by a change in the dose.
MICHAELIS-MENTEN
KINETICS
Elimination of drug by a saturable
enzymatic process
Describes the velocity of enzyme
reactions
MICHAELIS-MENTEN
KINETICS





WHERE:
ERate = elimination rate
V
max
= maximum elimination rate
C
p
= plasma concentration
K
M
= Michaelis constant
MICHAELIS-MENTEN
KINETICS


At low Cp values, the elimination
rate becomes first order



At high Cp values, the elimination
rate becomes zero order


CHRONOPHARMACOKINETICS
AND TIME-DEPENDENT
PHARMACOKINETICS
CHRONOPHARMACOKINETICS AND
TIME-DEPENDENT
PHARMACOKINETICS
Chronopharmacokinetics
broadly refers to a temporal change in
the rate process (such as absorption or
elimination) of a drug.
1. Cyclical - constant period (e.g.,
24-hour interval)
2. Noncyclical - which drug
absorption or elimination
changes over a longer period
of time.
CHRONOPHARMACOKINETICS AND
TIME-DEPENDENT
PHARMACOKINETICS
Time-dependent pharmacokinetics
refers to a noncyclical change in the drug
absorption or drug elimination rate
process over a period of time.
leads to nonlinear pharmacokinetics
It is the result of alteration in the
physiology or biochemistry in an
organ or a region in the body that
influences drug disposition
CHRONOPHARMACOKINETICS AND
TIME-DEPENDENT
PHARMACOKINETICS
Circadian rhythms
rhythmic or cyclical changes in plasma
drug concentrations that may occur daily,
due to normal changes in body functions
Some rhythmic changes that influence
body functions and drug response are
controlled by genes and subject to
modification by environmental factors
CHRONOPHARMACOKINETICS AND
TIME-DEPENDENT
PHARMACOKINETICS
Circadian rhythms
EXAMPLES:
Symptoms of hypoxemia may be
aggravated in some COPD
patients due to changes in
respiration during the sleep cycle
Platelet aggregation favoring
coagulation is increased after
arising in the early morning hours
early-morning rise in blood
pressure may increase the risk of
stroke or hypertensive crisis

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