Metabolism, disposition, excretion, and pharmacokinetics of levormeloxifene, a selective estrogen receptor modulator, in the rat.
The tissue distribution, pharmacokinetics, metabolism, and excretion of the selective estrogen receptor modulator levormeloxifene have been investigated after oral administration of [(14)C]-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.
Mountfield
R J
RJ
Department of Drug Metabolism, Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark. richard.mountfield@roche.com
Kiehr
B
B
John
B A
BA
D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D020847:Estrogen Receptor Modulators / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D008297:Male; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D020847:Estrogen Receptor Modulators; D011759:Pyrrolidines; C108255:levormeloxifene