RT Journal Article
SR Electronic
T1 Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1218
OP 1226
DO 10.1124/dmd.108.020404
VO 36
IS 7
A1 Chandra Prakash
A1 Kim A. Johnson
A1 Mark J. Gardner
YR 2008
UL http://dmd.aspetjournals.org/content/36/7/1218.abstract
AB Disposition of lasofoxifene, a next-generation selective estrogen receptor modulator, was investigated in male volunteers after p.o. 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 Tmax values typically exceeding 6 h. The Cmax and area under plasma concentration–time profile from time 0 to the last quantifiable time point 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 liquid chromatography/tandem mass spectrometry. The primary phase I metabolites were the result of 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 cytochromes P450 (P450s), and UDP glucuronosyltransferases (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 P450 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 (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). The American Society for Pharmacology and Experimental Therapeutics