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.

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.

Citation

M Reza Anari, Mellissa D Creighton, Jason S Ngui, Richard A Tschirret-Guth, Yohannes Teffera, George A Doss, Wei Tang, Nathan X Yu, Suzanne L Ciccotto, Donald F Hobra, John B Coleman, Stella H Vincent, David C Evans. 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. Drug metabolism and disposition: the biological fate of chemicals. 2006 Aug;34(8):1367-75

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PMID: 16698892

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