The in vitro metabolic kinetics of letrozole were investigated by incubating letrozole (10–500 μM) in female or male rat liver microsomes to assess the effect of gender and to predict the in vivo biotransformation characteristics of letrozole in rats. The effects of tamoxifen (TAM) on the metabolic kinetics of letrozole were also examined by incubating letrozole in female rat liver microsomes in the presence or absence of TAM. The effects of chronic pretreatment of female rats with TAM (0.5, 1.0, 5.0 mg/kg/day, i.p. for 7 consecutive days) on liver microsomal protein content and metabolic activity were also examined.
The formation rate of the carbinol metabolite of letrozole, CGP44 645, was significantly higher (p < 0.05) in male rat liver microsomes in comparison to female. The Vmax/Km ratio for letrozole metabolism in female rat liver microsomes did not change significantly (p > 0.05) in the presence of TAM. After chronic pretreatment of female rats with TAM (up to a dose of 1.0 mg/kg/day), the hepatic microsomal protein content was significantly increased but the formation rate of CGP44 645, when normalized for protein content, did not change significantly.
These results suggest that there is a marked gender difference in letrozole metabolism in rats. It also appears that acute treatment of female rat liver microsomes with TAM produces negligible inhibitory effect on the CYP mediated metabolic clearance of letrozole. However, chronic pretreatment of female rats with TAM appear to induce CYPs, but does not significantly impact the metabolic activities of the enzymes associated with the formation of the carbinol metabolite of letrozole.