Abstract
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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.009027.
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ABBREVIATIONS: S1P, sphingosine-1-phosphate; MRL-A, 1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid; MRL-B, 1-[6-methyl-5-(5-trifluoromethyl-4-phenyl-thiophen-2-ylmethoxy)-indane-1-yl]-azetidine-3-carboxylic acid; LC-MS/MS, liquid chromatography-tandem mass spectrometry; AUC, area under the curve; HPLC, high-performance liquid chromatography; FMO, flavin-containing monooxygenase; ABT-418, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole.
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↵1 Current affiliation: Amgen Inc., Cambridge, Massachusetts.
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↵2 Current affiliation: Drug Metabolism, Johnson & Johnson PRD, Raritan, New Jersey.
- Received December 28, 2005.
- Accepted May 9, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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