Received for publication January 9, 2008.
Revised March 24, 2008.
Accepted for publication March 25, 2008.

DISPOSITION OF LASOFOXIFENE, A NEXT GENERATION SELECTIVE ESTROGEN RECEPTOR MODULATOR, IN HEALTHY MALE SUBJECTS

Abstract

Disposition of lasofoxifene, a next generation selective estrogen receptor modulator, was investigated in male volunteers after oral administration of a single 20 mg dose of [¹⁴C]lasofoxifene. Approximately 72% of the administered dose was recovered from the urine and feces, with majority of dose excreted in the feces probably via bile. The absorption of lasofoxifene in humans was slow with T_max values typically exceeding 6 h. The C_max and AUC_(0-tlast) values of lasofoxifene were lower than those determined for total radioactivity, indicating presence of circulating metabolites. The primary clearance mechanisms for lasofoxifene in humans were direct conjugation (glucuronide and sulfate conjugates) and phase I oxidation, each accounting for about half of the metabolism. Several oxidative metabolites were identified by LC/MS/MS. The primary phase I metabolites were due to hydroxylations on the tetraline moiety and the phenyl rings attached to the tetraline, and oxidation on the pyrrolidine moiety. Considering the numerous metabolites seen in vivo, additional in vitro studies using human liver and intestinal microsomes, recombinant CYPs and UGTs were performed. The turnover of lasofoxifene was very slow in liver microsomes and only two metabolites were identified as two regioisomers of the catechol metabolite. The results from in vitro experiments with recombinant isoforms and CYP-isoform selective inhibitors suggested that the oxidative metabolism of lasofoxifene is catalyzed primarily by CYP3A and CYP2D6. In addition, its glucuronidation is catalyzed by UGTs that are expressed in both the liver (1A1, 1A3, 1A6 and 1A9), and the intestine (1A8 and 1A10).

Key words: cytochrome P450 catalyzed oxidations, drug disposition, excretion, glucuronidation, human CYP enzymes, metabolite identification, microsomes, phase II drug metabolism, sulfate conjugation