RT Journal Article SR Electronic T1 Pharmacokinetics and Metabolism of the Novel Anticonvulsant AgentN-(2,6-Dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in Rats and Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 40 OP 46 VO 25 IS 1 A1 Steven W. Martin A1 Frances E. Bishop A1 Brad M. Kerr A1 Markus Moor A1 Martha Moore A1 Pamela Sheffels A1 Mohammed Rashed A1 J. Greg Slatter A1 Laurence Berthon-Cédille A1 Francis Lepage A1 Jean-Jacques Descombe A1 Michel Picard A1 Thomas A. Baillie A1 René H. Levy YR 1997 UL http://dmd.aspetjournals.org/content/25/1/40.abstract AB N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) belongs to a new series of experimental anticonvulsants related to lidocaine. This study was undertaken to understand the pharmacokinetics and metabolism of D2624 in rats and humans, with emphasis on the possible formation of 2,6-dimethylaniline (2,6-DMA). After oral administration of stable isotope-labeled parent drug to rats and GC/MS analysis of plasma samples, two metabolites were identified: D3017, which is the primary alcohol, and 2,6-DMA, formed by amide bond hydrolysis of either D2624 or D3017. In urine, three metabolites of D2624 were identified: namely D3017, 2,6-DMA, and D3270 (which is the carboxylic acid derivative of D3017). Based on plasma AUC analysis, D3017 and 2,6-DMA accounted for >90% of the dose of D2624. After oral administration, D2624 was found to be well absorbed (93%), but underwent extensive first-pass metabolism in the rat, thus resulting in 5.3% bioavailability. Rat and human liver microsomal preparations were capable of metabolizing D2624 to D3017 and 2,6-DMA. The formation of D3017 was NADPH-dependent, whereas 2,6-DMA formation was NADPH-independent and probably was catalyzed by amidase(s) enzymes. In a single-dose (25–225 mg) human volunteer study, the parent drug (D2624) was not detected in plasma at any dose, whereas 2,6-DMA was detected only at the two highest doses (150 and 225 mg). D3017 was detected after all doses of parent drug, with approximate dose proportionality in AUC and a half-life of 1.3–2.2 hr. The metabolic behavior observed in humans suggests there is a marked species difference in the oxidative and hydrolytic pathways of D2624. The American Society for Pharmacology and Experimental Therapeutics