N-oxidation of N-methylpyrrolidine Released in Vivo from Cefepime

Cefepime (BMY-28142), 7-[alpha-(2-aminothiazol-4-yl)-alpha-(Z)-methoximin oacetamido] -3-[(1-methyl-1-pyrrolidino)-methyl]-3-cephem-4-carboxylate is a potent cephalosporin that is unique in having a quaternized N-methylpyrrolidino side chain. Degradation of the beta-lactam ring can result in release of N-methylpyrrolidine (NMP), an alicyclic tertiary amine. After iv bolus administration of [methyl-14C]NMP, most radioactivity in the urine of rats and a dog was present as a polar, nonextractable metabolite, which was isolated and identified as NMP N-oxide. A minor urinary metabolite was not identified. The NMP concentration in plasma declined in a rapid monoexponential manner, and there was a concomitant increase in the N-oxide concentration. After iv administration of cefepime, which was labeled with 14C in the methyl group of the NMP side chain, 86% of the radiolabel recovered in the urine was attributable to intact antibiotic. The balance was principally present as the N-oxide. Oxidation of NMP to the N-oxide by rat and human liver microsomes was demonstrable in vitro. These results indicate that intravenously administered NMP or NMP arising from the degradation of cefepime in vivo is subject to rapid metabolic clearance.