SEX DIFFERENCE IN METABOLISM OF SIMVASTATIN BY RAT HEPATIC MICROSOMES

Metabolism of simvastatin (SV), a new cholesterol-lowering agent, by hepatic microsomes from male and female rats was investigated. After incubation of [C-14]-SV with hepatic microsomes, radioactive metabolites were detected by HPLC. The main metabolite was 3'alpha-hydroxy-SV in male rats and the hydroxy open acid form of SV (SVA) in females. The 3''-hydroxy-SV and 3'3''-dihydroxy-SV which were observed in male rats were hardly detected in females. Specific activity for the metabolism of SV in male rats (3.97 nmol/mg protein/min) was about 9-times higher than that in females. Metabolic activity of hepatic microsomes in male rats was essentially unchanged with increase in age, whereas that in females decreased age-dependently and was very low or negligible after 7 weeks of age. Formation of 3''-hydroxy-SV and 3,3''-dihydroxy-SV in male rats was markedly increased with age, and that in females was negligible at all ages examined.