Pharmacokinetics of raloxifene in male Wistar–Hannover rats: Influence of complexation with hydroxybutenyl-beta-cyclodextrin

Raloxifene is a highly insoluble, highly metabolized serum estrogen receptor modulator approved for use in the treatment of osteoporosis. Hydroxybutenyl-beta-cyclodextrin (HBenBCD) is a novel solubility enhancer previously demonstrated to increase the oral bioavailability of tamoxifen, letrozole, and itraconazole. The current study evaluated the pharmacokinetics of raloxifene in oral and intravenous formulations with HBenBCD in male Wistar–Hannover rats. Analytical methodology to measure raloxifene and its metabolites was developed by measuring raloxifene metabolism in vitro. Formulation with HBenBCD significantly increased raloxifene oral bioavailability. Mean ± S.D. oral bioavailabilities were 2.6 ± 0.4% for raloxifene formulated with microcrystalline cellulose, 7.7 ± 2.1% for a solid capsule formulation of raloxifene:HBenBCD complex, and 5.7 ± 1.3% for a liquid-filled capsule formulation containing raloxifene:HBenBCD/PEG400/H 2O. Relative to raloxifene/microcrystalline filled capsules, the presence of HBenBCD in the solid capsule formulation afforded: (i) a decrease in raloxifene T max (2.5 ± 0.5 h versus 4.0 ± 0.5 h); (ii) a two-fold increase in raloxifene C max and a three-fold increase in raloxifene AUC; and (iii) a 12-fold increase in raloxifene glucuronide C max and a 6.5-fold increase in raloxifene glucuronide AUC. Hence, these studies demonstrate that raloxifene formulations containing HBenBCD significantly increased the oral bioavailability in rats relative to formulations that did not contain HBenBCD.