Paxil - Clinical Pharmacology

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In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.

The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified.

Data indicate that the metabolites have no more than 1/ 50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by cytochrome P450IID6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.

About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-closing period.

Distribution

Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.

Protein Binding

Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/ mL and 400 ng/ mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/ mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.