Abstract
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.
Footnotes
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Send reprint requests to: Dr. R.J. Mountfield, F. Hoffman-La Roche Ltd, Pharmaceuticals Division, Granzacher Str. 124, CH 4002 Basel, Switzerland. E-mail: richard.mountfield{at}roche.com
- Abbreviations used are::
- ERT
- estrogen replacement therapy
- LC-MS-MS
- liquid chromatography-tandem mass spectrometry
- WBA
- whole body autoradiography
- AUC
- area under the plasma concentration versus time curve
- APCI
- atmospheric pressure chemical ionization
- Received July 22, 1999.
- Accepted January 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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