8.2 : Nonlinear Pharmacokinetics: Causes of Nonlinearity

Nonlinearity in drug pharmacokinetics is caused by various factors influencing how a drug is absorbed, distributed, metabolized, and excreted. Understanding these nonlinear processes is crucial for predicting drug behavior in the body and optimizing drug dosing regimens.

Nonlinear drug absorption can occur when the process is rate-limited by solubility, carrier-mediated transport systems, or saturation of the presystemic gut wall or hepatic metabolism. For instance, high doses of riboflavin (vitamin B2) can saturate presystemic metabolism, leading to increased bioavailability. This means that a small change in the dose of riboflavin can result in a large variation in its plasma concentration.

Nonlinear distribution occurs due to the saturation of binding sites on plasma proteins or tissue binding sites. Phenylbutazone (Butazolidine), a nonsteroidal anti-inflammatory drug, provides an example of this phenomenon. Phenylbutazone can saturate its plasma protein binding sites at high concentrations, increasing the drug's unbound fraction. This unbound fraction is pharmacologically active and can lead to enhanced therapeutic effects or potential toxicity.

Nonlinearity in metabolism can arise from capacity-limited metabolism due to enzyme saturation or induction. Carbamazepine (Tegretol), an anticonvulsant and mood-stabilizing drug, is a prime example. Repetitive administration of carbamazepine can induce its own metabolism, leading to a decrease in peak plasma concentration. This phenomenon, known as autoinduction, can affect drug efficacy and requires dose adjustments.

Nonlinear renal excretion can occur due to saturation of the tubular carrier system. When transporters involved in the reabsorption of glucose and water-soluble vitamins become saturated, they can increase renal clearance of these substances.

Pathological changes can also cause nonlinear kinetics. For instance, aminoglycosides, a class of antibiotics, can induce renal nephrotoxicity, which alters renal drug excretion. This can affect the clearance of drugs primarily excreted by the kidneys, leading to their accumulation and potential toxicity.