The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.

A study on guinea pigs examined the dose-dependent pharmacokinetics of sodium valproate (VPA) and found that at higher doses, the area under the plasma concentration-time curve increased disproportionately. Total clearance decreased significantly while the beta elimination half-life increased. This dose-dependent behavior of VPA was attributed to saturation of metabolism, which was markedly reduced in young guinea pigs.

Similar enzymatic saturation may be observed in infants and special patient populations, leading to linear drug metabolism with dose variations in normal subjects. Paroxetine hydrochloride, an orally administered psychotropic drug, undergoes extensive metabolism via CYP2D6. With increasing doses, nonlinearity in pharmacokinetics is observed due to autoinhibition. The elimination half-life of paroxetine is approximately 21 hours. Saturation of CYP2D6 at clinical doses contributes to the nonlinear kinetics of paroxetine, along with extended treatment duration. This enzyme's role in paroxetine metabolism also suggests potential drug-drug interactions.

Clinical studies have shown that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6, including desipramine, risperidone, and atomoxetine. Paroxetine hydrochloride is known to inhibit the metabolism of selective serotonin reuptake inhibitors and monoamine oxidase inhibitors, which can result in serotonin syndrome.

Accidental overdosing with paroxetine hydrochloride has been reported, where high liver drug concentrations and extensive tissue distribution make it challenging to remove the drug. Saturation of CYP2D6 can lead to disproportionately higher plasma levels than expected from an increase in dosage. These elevated plasma drug concentrations may exceed the recommended 20-50 mg range.

Understanding drug dose-dependent pharmacokinetics and nonlinear kinetics is crucial for optimizing dosing strategies, managing drug interactions, and minimizing the risk of adverse effects.