Pharmacokinetics of letrozole in male and female rats: influence of complexation with hydroxybutenyl-beta-cyclodextrin

Cyclodextrins (CDs) are one of the most successful solutions to the problem of poor drug solubility. In this study, we examined the in-vitro effects of three CDs on the solubility of letrozole, a breast cancer drug that is practically insoluble in water. The most promising, hydroxybutenyl-beta-cyclodextrin (HBen beta CD), was used for in-vivo studies in male and female Sprague-Dawley rats. Letrozole is a drug with dramatic gender-based differences in pharmacokinetics. For example, the terminal half-life (t1/2) of letrozole following intravenous administration in male rats was 11.5 +/- 1.8 h (n = 3), while in female rats it was 42.3 +/- 2.9 h (n = 3). HBen beta CD increased the solubility and enhanced the dissolution rate of letrozole. Complexation of letrozole with HBen beta CD improved oral absorption in male rats and maximized absorption in female rats. Regardless of gender, the presence of HBen beta CD in the formulation increased the in-vivo rate of absorption. When administered in a capsule formulation with letrozole, HBen beta CD resulted in a higher C-max (61% in male rats, 42% in female), shorter T-max values (8.4 to 6.3 h in male, 16.4 h to 5.4 h in female) and increased absolute oral bioavailability (46 +/- 2 vs 38 +/- 3 in male, 101 +/- 3 vs 95 +/- 2 in female). Thus, solubility limits both rate and extent of letrozole absorption in male rats, but limits only the rate of absorption in female rats.