Vol. 28, Issue 5, 503-513, May 2000

Metabolism, Disposition, Excretion, and Pharmacokinetics of Levormeloxifene, A Selective Estrogen Receptor Modulator, in the Rat

Richard J. Mountfield, Benedicte Kiehr, and Brian A. John

Departments of Drug Metabolism (R.J.M.) and Pharmacokinetics (B.K.), Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark; and Department of Drug Metabolism, HLS Ltd, Huntingdon, Cambridgeshire, England (B.A.J.)

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, plasma C_max 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.