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Drug Metabolism and Disposition Fast Forward
First published on May 12, 2006; DOI: 10.1124/dmd.105.009027

0090-9556/06/3408-1367-1375$20.00
DMD 34:1367-1375, 2006

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SPECIES DIFFERENCES IN METABOLISM AND PHARMACOKINETICS OF A SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONIST IN RATS AND DOGS: FORMATION OF A UNIQUE GLUTATHIONE ADDUCT IN THE RAT

M. Reza Anari, Mellissa D. Creighton, Jason S. Ngui, Richard A. Tschirret-Guth, Yohannes Teffera1, George A. Doss, Wei Tang, Nathan X. Yu, Suzanne L. Ciccotto, Donald F. Hobra, Jr., John B. Coleman, Stella H. Vincent, and David C. Evans2

Department of Drug Metabolism (M.R.A.) and Department of Safety Assessment (J.B.C.), Merck Research Laboratories, West Point, Pennsylvania; and Department of Drug Metabolism (M.D.C., J.S.N., R.A.T.-G., Y.T., G.A.D., W.T., N.X.Y., S.L.C., S.H.V., D.C.E.) and Department of Comparative Medicine (D.F.H.), Merck Research Laboratories, Rahway, New Jersey

The pharmacokinetics and metabolism of 1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid (MRL-A), a selective agonist for the sphingosine-1-phosphate 1 (S1P1) receptor, were investigated in rats and dogs. In both species, more than 50% of the dose was excreted in bile. Specific to the rat, and observed in bile, were a taurine conjugate of MRL-A and a glucuronide conjugate of an azetidine lactam metabolite. In dogs, a smaller portion of the dose (54% of administered dose) was excreted intact in bile, and the major metabolites detected were an azetidine N-oxide of MRL-A and an acylglucuronide of an N-dealkylation product. This latter metabolite was also observed in rat bile. Stereoselective formation of the N-oxide isomer was observed in dogs, whereas the rat produced comparable amounts of both isomers. The formation of a unique glutathione adduct was observed in rat bile, which was proposed to occur via N-dealkylation, followed by reduction of the putative aldehyde product to form the alcohol, and dehydration of the alcohol to generate a reactive quinone methide intermediate. Incubation of a synthetic standard of this alcohol in rat microsomes fortified with reduced glutathione or rat hepatocytes resulted in formation of this unique glutathione adduct.

Address correspondence to: M. Reza Anari, Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, PA 19486. E-mail: reza_anari{at}yahoo.com






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