Sex difference in the metabolism of pirmenol in rats

The in vitro metabolism of pirmenol (cis-alpha-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyri dinemethanol) and glucuronidation of its metabolites, a 4-hydroxylated derivative of pirmenol (M3) and 3-methylether of M3 (M5), were investigated using a hepatic 9000 x g supernatant and microsomes, respectively, of female and male rats in order to elucidate the higher urinary excretion of M3G and M5G (glucuronides of M3 and M5, respectively) in females previously observed in in vivo metabolism. Pirmenol delta1' iminium ion (M2) and M3 were formed by the oxidation of pirmenol in both sexes; however, M2 was the main metabolite in males, while M2 and M3 were formed at nearly the same level in females. On glucuronidation of M3 and M5, the Vmax values of both compounds were higher in female rats, consistent with the results in vivo. In addition, the sex difference in the urinary excretion ratio of M5G to M3G (1.1 in female, 2.5 in male) might reflect the lower availability of M3 for glucuronidation in male rats in vivo. The chromatographic separation of diastereomers of M5G was also described.