Interspecies comparison of pharmacokinetic profile and bioavailability of (+/-)-gossypol in male Fischer-344 rats and male B6C3F mice.

Gossypol is a naturally occurring yellow substance in cotton plant that has male reproductive toxicity both in humans and some experimental animal species. Interspecies oral bioavailability and pharmacokinetic profile of (+/-)-gossypol were compared in male Fischer-344 rats and B6C3F mice after a 1) single intravenous dose, 2) single oral dose, and 3) 14 consecutive, daily, oral doses; all doses were 10 and 50 mg/kg rats and mice, respectively. In both species, the intravenous plasma (+/-)-gossypol concentrations showed a triexponential pattern, indicating a 3-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous injection was 9.1 h and 7.7 h in rats and mice, respectively. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma after a single intravenous injection were 1.84 and 1.23 l/h per kg, 0.20 and 1.74 l/kg, and 36.0 and 115.8 mg.h/l, in rats and mice, respectively. The bioavailability of a single, oral dose of (+/-)-gossypol was 86% and 14.3% in rats and mice, respectively. In rats the change in plasma (+/-)-gossypol concentration after a single, dose was monophasic; multiple doses showed a biphasic pattern. In mice a single, dose of (+/-)-gossypol showed a biexponential plasma concentration pattern; daily dosing was monoexponential and was eliminated twice as fast as the single dose. Also, multiple doses of (+/-)-gossypol in the mouse were eliminated 7 times faster than in the rat. These findings are consistent with previous results that daily, oral dosing of (+/-)-gossypol, but not a single dose, produces infertility in the male rat, while the mouse is insensitive to (+/-)-gossypol action. The results of this study indicate that differential sensitivity of rats and mice to the contraceptive action of (+/-)-gossypol may be related, at least in part, to its pharmacokinetic profiles in both species.