Gender-related differences in stereoselective degradation of flutriafol in rabbits

The stereoselective pharmacokinetics of flutriafol were investigated in male and female adult Japanese white rabbits. Following intravenous administration of rac-flutriafol to rabbits at 5 mg/kg (bd wt), the concentrations of the enantiomers in plasma were determined by a HLPC-UV method using a CDMPC-CSP chiral column. R-Flutriafol exhibited a shorter distribution half-life but a longer elimination half-life than the S-isomer. In female rabbits, the distribution half-lives of R- and S-flutriafol were found to be 0.09 and 0.18 h, respectively, significantly shorter than those in male rabbits, but the volume of distribution and elimination half-life for flutriafol enantiomers in both sexes of rabbit showed no significant differences. Female rabbits had a higher clearance for both flutriafol enantiomers. The protein binding value was high for both isomers, with enantioselectivity, but no gender difference. It was an important factor in modulating the disposition of flutriafol. Flutriafol concentrations in kidney, liver, fat, and lung were higher than in other tissues at 10 h after administration, and the concentrations of R-flutriafol were higher in all tissues than those of its antipode. However, gender difference in flutriafol residues in tissues was not observed. It is concluded that the stereoselectivity of flutriafol on distribution and elimination in rabbits mainly depends upon gender.