Causes of Nonlinearity

CAUSES OF NONLINEARITY

Nonlinearities can occur in drug absorption, distribution, metabolism and excretion.

Drug Absorption

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, K_a, C_max 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.

Drug Distribution

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 V_d 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.

Drug Metabolism

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 Cl_H and therefore increased C_ss. 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.

Drug Excretion

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.