Biotransformation and pharmacokinetics in the rhesus monkey of 2-n-propyl-4-pentenoic acid, a toxic metabolite of valproic acid.

2-n-Propyl-4-pentenoic acid (delta 4-VPA), a hepatotoxic metabolite of valproic acid (VPA), was administered by iv bolus injection (14 mg kg-1) to two adult male rhesus monkeys. The plasma concentration vs. time curve for delta 4-VPA in these animals was biexponential and the effective half-life values were 0.53 and 0.67 hr. The pharmacokinetic profile of delta 4-VPA was similar to that of VPA in the monkey, although the unbound fraction of delta 4-VPA in plasma was approximately 2.5-fold greater than the value for the parent drug. The major route of elimination of delta 4-VPA was excretion into urine, and studies with a group of eight animals indicated that delta 4-VPA undergoes extensive biotransformation in this species. A total of 20 metabolites was detected in urine by GC-MS techniques, and 19 of these were identified positively by comparison of their gas-liquid chromatographic and mass spectrometric properties with those of the authentic compounds prepared by synthesis. Many of these metabolites were present largely in the form of glucuronide conjugates, as was delta 4-VPA itself. The major pathways of metabolism of delta 4-VPA were found to be ester glucuronide formation and beta-oxidation, whereas omega- and (omega-1)-oxidation processes were of minor quantitative importance. Excretion of unchanged drug and its metabolites into urine over 24 hr accounted collectively for some 59% of the administered dose, a figure which was appreciably less than the corresponding recovery of metabolites of VPA in the same monkeys. The possibility is raised that beta-oxidation of delta 4-VPA leads to the generation of a chemically reactive intermediate(s) which alkylate(s) cellular macromolecules and thereby forms tissue-bound residues. The significance of such a phenomenon is discussed in relation to the etiology of VPA-induced liver injury.