PT  - JOURNAL ARTICLE
AU  - Richard J. Mountfield
AU  - Benedicte Kiehr
AU  - Brian A. John
TI  - Metabolism, Disposition, Excretion, and Pharmacokinetics of Levormeloxifene, A Selective Estrogen Receptor Modulator, in the Rat
DP  - 2000 May 01
TA  - Drug Metabolism and Disposition
PG  - 503--513
VI  - 28
IP  - 5
4099  - http://dmd.aspetjournals.org/content/28/5/503.short
4100  - http://dmd.aspetjournals.org/content/28/5/503.full
SO  - Drug Metab Dispos2000 May 01; 28
AB  - The tissue distribution, pharmacokinetics, metabolism, and excretion of the selective estrogen receptor modulator levormeloxifene have been investigated after oral administration of [14C]-levormeloxifene to male and female Sprague-Dawley rats. The quantitative distribution of radiolabeled levormeloxifene and/or metabolites was confirmed by whole body autoradiography. Levormeloxifene was absorbed from the gastrointestinal tract and was widely distributed into tissues, with peak radioactive concentrations generally being observed 4 h after administration in the intestine, liver, lung, kidney, spleen, pancreas, adrenals, and ovary (females). Fecal elimination was the major excretion route of radioactivity. In a separate pharmacokinetic study, plasmaCmax was generally observed 6 h after dose administration and the half-life of elimination was long (24 h) and a doubling in dose resulted in an approximate doubling in exposure. The majority of the drug was excreted as norlevormeloxifene; the 7-desmethyl metabolite of levormeloxifene, via the formation of phase II metabolites (glucuronides) and excretion into the bile. Unchanged drug was also excreted, mainly from 0 to 24 h, and accounted for about 6 to 12% of the dose. Together these two components accounted for approximately 50% of the radioactivity excreted. Additional metabolites isolated and identified by liquid chromatography-tandem mass spectrometry, and accounting for 1 to 5% of the excreted radioactivity in rat feces during the first 24 h, included two monohydroxylevormeloxifene species, a pyrrolidinone ring-opened metabolite of levormeloxifene, and desmethylnorlevormeloxifene. The American Society for Pharmacology and Experimental Therapeutics