Pharmacokinetic profile of (+/-)-gossypol in male Sprague-Dawley rats following single intravenous and oral and subchronic oral administration.
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 (Vd), and AUCplasma 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 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.
Othman
M A
MA
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Abou-Donia
M B
MB
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003272:Contraceptive Agents, Male / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006072:Gossypol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism*
D003272:Contraceptive Agents, Male; D006072:Gossypol