Fractions metabolized in a triangular metabolic system: cinromide and two metabolites in the rhesus monkey

Abstract

A previous study of the metabolic fate of cinromide (3-bromo-N-ethylcinnamamide) in rhesus monkey established that half of a dose is metabolized by N-deethylation to an active metabolite, 3-bromocinnamamide. Both cinromide and its proximal metabolite can be metabolized by amide hydrolysis to a second metabolite, 3-bromocinnamic acid, resulting in a triangular metabolic problem. This investigation was undertaken to distinguish between these two nonexclusive possibilites. A preliminary study was carried out to characterize the pharmacokinetics of 3-bromocinnamic acid. In the main study, six monkeys received an intravenous dose of cinromide, 3-bromocinnamamide, and 3-bromocinnamic acid in a randomized order. The time courses of compound administered and corresponding metabolites were followed. The following fractions of dose metabolized (mean +/- SD) were obtained: cinromide to 3-bromocinnamide: 0.53 +/- 0.24; 3-bromocinnamamide to 3-bromocinnamic acid: 0.53 +/- 0.21; cinromide to 3-bromocinnamic acid directly: 0.48 +/- 0.32. Thus, it was found that 3-bromocinnamic acid is formed directly from cinromide and from 3-bromocinnamamide. Also, as primary metabolites, 3-bromocinnamic acid and 3-bromocinamamide account for all of a cinromide dose with a mean value of 1.00 +/- 0.34. The observed variability in these fractions metabolized was explained by the fact that in the solution of the triangular metabolic problem, three clearances are assumed to remain constant over three studies.