Abstract

Disposition of traxoprodil ({1-[2-hydroxy-2-(4-hydroxy-phenyl)-1-methyl-ethyl]-4-phenyl-piperidin-4-ol}mesylate; TRX), a selective antagonist of the N-methyl-d-aspartate class of glutamate receptors, was investigated in rats and dogs after administration of a single i.v. bolus dose of [¹⁴C]TRX. Total mean recoveries of the radiocarbon were 92.5 and 88.2% from rats and dogs, respectively. Excretion of radioactivity was rapid and nearly complete within 48 h after dosing in both species. Whole-body autoradioluminography study suggested that TRX radioactivity was retained more by uveal tissues, kidney, and liver than by other tissues. TRX is extensively metabolized in rats and dogs since only 8 to 15% of the administered radioactivity was excreted as unchanged drug in the urine of these species. The metabolic pathways included aromatic hydroxylation at the phenylpiperidinol moiety, hydroxylation at the hydroxyphenyl ring, and O-glucuronidation. There were notable species-related qualitative and quantitative differences in the metabolism of TRX in rats and dogs. The hydroxylation at the 3-position of the phenol ring followed by methylation of the resulting catechol intermediate and subsequent conjugation were identified as the main metabolic pathways in dogs. In contrast, formation of the major metabolites in rats was due to oxidation at the 4′-position of the phenylpiperidinol moiety followed by further oxidation and phase II conjugation. TRX glucuronide conjugate was identified as the major circulating component in rats, whereas the glucuronide and sulfate conjugates of O-methyl catechol metabolite were the major metabolites in dog plasma. The site of conjugation of regioisomeric glucuronides was established from the differences in the collision-induced dissociation product ion spectra of their methylated products.