Effect of gonadectomy and hormones on sex differences in ketoprofen enantiomer glucuronidation and renal excretion of formed glucuronides in the rat.

Abstract

To investigate the sex hormone dependency of phase II metabolism using S-ketoprofen (S-KT) urinary excretion (sigmaXu) as a marker in the rat. The effect of surgical gonadectomy, with or without concomitant estradiol or testosterone treatment, on the sigmaXu of glucuronidated S-KT was studied in male and female rats. Hepatic and renal glucuronidation of KT enantiomers was also determined using microsomal preparations from these animals. A controlling effect of testosterone was demonstrated by a rapid increase in sigmaXu of glucuronidated S-KT in castrated males (27.9 +/- 9.0%) compared to control males (7.2 +/- 3.9%). This approximated control female excretion (40.5 +/- 11.6%). Treatment of ovarectomized females with testosterone resulted in a steady reduction in sigmaXu of glucuronidated S-KT with time (13.4 +/- 5.4% at end point). Hepatic glucuronidation of S-KT by male rat liver microsomes was significantly higher than that of female, whereas renal glucuronidation of S-KT by female rat kidney microsomes was significantly higher than that of male. Significant correlations were found between hepatic (r = -0.78) or renal (r = 0.83) glucuronidation and sigmaXu of glucuronidated S-KT. Urinary excretion of S-KT-GC is sex hormone-dependent. This metabolite may have utility as a marker or probe for sex hormone-dependent studies of phase II metabolism.