Nonlinearities can occur in drug absorption, distribution, metabolism and excretion.
CAUSES OF NONLINEARITY
Nonlinearities can occur in drug absorption,
distribution, metabolism and excretion.
Nonlinearity in drug absorption can arise from 3
important sources –
1. When absorption is solubility or dissolution rate-limited e.g. griseofulvin. At higher
doses, a saturated solution of the drug is formed in the GIT or at any other
extravascular site and the rate of absorption attains a constant value.
2. When absorption involves carrier-mediated transport systems e.g. absorption of riboflavin,
ascorbic acid, cyanocobalamin, etc. Saturation of the transport system at
higher doses of these vitamins results in nonlinearity.
3. When presystemic gut wall or hepatic metabolism attains saturation e.g. propranolol, hydralazine
and verapamil. Saturation of presystemic metabolism of these drugs at high
doses leads to increased bioavailability.
The parameters affected will be F, Ka, Cmax
and AUC. A decrease in these parameters is observed in the former two cases and
an increase in the latter case. Other causes of nonlinearity in drug absorption
are changes in gastric emptying and GI blood flow and other physiologic
factors. Nonlinearity in drug absorption is of little consequence unless
availability is drastically affected.
Nonlinearity in distribution of drugs administered
at high doses may be due to –
1. Saturation of binding sites on plasma proteins e.g. phenylbutazone and naproxen. There
is a finite number of binding sites for a particular drug on plasma proteins
and, theoretically, as the concentration is raised, so too is the fraction
unbound.
2. Saturation of tissue binding sites e.g.
thiopental and fentanyl. With large single
bolus doses or multiple dosing, saturation of tissue storage sites can
occur.
In both cases, the free plasma drug concentration
increases but Vd increases only in the former case whereas it decreases
in the latter. Clearance is also altered depending upon the extraction ratio of
the drug. Clearance of a drug with high ER is greatly increased due to
saturation of binding sites. Unbound clearance of drugs with low ER is
unaffected and one can expect an increase in pharmacological response.
The nonlinear kinetics of most clinical importance
is capacity-limited metabolism since small changes in dose administered can
produce large variations in plasma concentration at steady-state. It is a major
source of large intersubject variability in pharmacological response.
Two important causes of nonlinearity in metabolism
are –
1. Capacity-limited metabolism due to enzyme and/or cofactor saturation. Typical examples include
phenytoin, alcohol, theophylline, etc.
2. Enzyme induction e.g. carbamazepine, where a
decrease in peak plasma concentration
has been observed on repetitive administration over a period of time.
Autoinduction characterized in this case is also dose-dependent. Thus, enzyme
induction is a common cause of both dose- and time-dependent kinetics.
Saturation of enzyme results in decreased ClH
and therefore increased Css. Reverse is true for enzyme induction.
Other causes of nonlinearity in biotransformation include saturation of binding
sites, inhibitory effect of the metabolite on enzyme and pathologic situations
such as hepatotoxicity and changes in hepatic blood flow.
The two active processes in renal excretion of a
drug that are saturable are –
1. Active tubular secretion e.g.
penicillin G. After saturation of the carrier system, a decrease in renal clearance occurs.
2. Active tubular reabsorption e.g.
water soluble vitamins and glucose. After
saturation of the carrier system, an increase in renal clearance occurs.
Other sources of nonlinearity in renal excretion
include forced diuresis, changes in urine pH, nephrotoxicity and saturation of
binding sites.
Biliary secretion, which is also an active process,
is also subject to saturation e.g. tetracycline and indomethacin.
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