Pharmacokinetic Profile of (±)-Gossypol in Male Sprague-Dawley Rats following Single Intravenous and Oral and Subchronic Oral Administration

Abstract

The pharmacokinetic profile of (±)-gossypol was determined in male Sprague-Dawley rats following a single intravenous or oral 10 mg/kg dose and after receiving a daily oral 10 mg/kg dose for 14 days. The intravenous plasma (±)-gossypol level data were fitted with a three-compartment, open-model system. The apparent half-life of elimination of (±)-gossypol following intravenous administration was 11.44 hr, corresponding to an elimination rate constant of 0.05 hr^-1. The total plasma clearance (Cl), volume of distribution (V _d), and AUC_plasma following a single intravenous administration were 0.16 liter/hr/kg, 0.05 liter/kg, and 63.09 mg·hr/liter, respectively. The bioavailability of a single oral dose of (±)-gossypol in rats was 60%. The change in plasma (±)-gossypol concentration after a single or after multiple doses showed a biphasic pattern. A single oral dose of (±)-gossypol, however, was eliminated five times faster than the daily administered chemical. Thus, a single oral dose of (±)-gossypol was eliminated at a rate constant of 0.01 hr^-1, corresponding to a half-life of 64.76 hr. Subchronic oral administration of (±)-gossypol showed an apparent half-life of 101.91 hr^-1, corresponding to a rate constant of 0.007 hr^-1. The results indicate that multiple oral dosing of (±)-gossypol resulted in its longer retention in body tissue than a single oral dose. This study suggests that pharmacokinetics of (±)-gossypol may play, at least in part, a role in the reproductive toxicity of Subchronic but not single oral dosing.