A comparative investigation of 2-propyl-4-pentenoic acid (4-ene VPA) and its alpha-fluorinated analogue: phase II metabolism and pharmacokinetics

An earlier study in rats revealed that alpha-fluorination of 2-propyl-4-pentenoic acid (4-ene VPA), a toxic metabolite of the anticonvulsant drug valproic acid, would avert its metabolism via beta-oxidation and eliminate the drug-related hepatotoxicity. This investigation was carried out to compare 4-ene VPA and the alpha-fluorinated analogue (alpha-fluoro-4-ene VPA) for their pharmacokinetic and protein binding properties. Male Sprague-Dawley rats were dosed with either 4-ene VPA or alpha-fluoro-4-ene VPA i.p. at 1.4 mmol/kg. Blood was collected from the tail vein at various time points and serum samples were prepared. Urine was collected for 24 hr. A second set of rats was treated the same but sacrificed 1 hr post dose, and the livers were homogenized in a Tris-buffer. Protein binding was assessed via ultrafiltration of the naive serum samples spiked with either of the drugs. The serum drug concentration-time profiles of 4-ene VPA and alpha-fluoro-4-ene VPA seemed to resemble one another during the initial 200 min within which differences were reported for their effects on mitochondrial GSH. A second serum peak concentration was observed for 4-ene VPA at approximately 300 min, which was attributed to the extensive glucuronidation of the drug and enterohepatic circulation. The alpha-fluoro-4-ene VPA, on the other hand, did not show these properties with its major phase II metabolite being the corresponding L-glutamine conjugate. The toxic metabolite (E)-2-propyl-2,4-pentadienoic acid and its N-acetylcysteine conjugate were detected only in 4-ene VPA treated rats. Liver concentrations of 4-ene VPA and alpha-fluoro-4-ene VPA were 0.96 +/- 0.11 and 0.89 +/- 0.19 micromol/g of wet liver, respectively, at 1 hr after the dose. Comparable and parallel serum free drug levels were apparent for the two drugs over a concentration range of 0.25 to 2.9 micromol/ml. Taken together, the data seem to suggest that the reported distinction in the ability of 4-ene VPA and alpha-fluoro-4-ene VPA to produce liver toxicity in the rat resides in differences in their metabolism rather than in their pharmacokinetic properties.