Pharmacokinetic analysis of ester prodrugs of valproic acid

The pharmacokinetics of five monoester prodrugs of valproic acid (VPA) were investigated: propyl valproate (P‐VPA), butyl valproate (B‐VPA), isobutyl valproate (IB‐VPA), isoamyl valproate (IA‐VPA), and hexyl valproate (H‐VPA). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPA and valpromide (VPD). The pharmacokinetics of VPA and its five ester derivatives were determined after intravenous administration of equivalent doses (400 mg of VPA) to six dogs. The five ester prodrugs of VPA were biotransformed to VPA; the biotransformation was complete for P‐VPA, B‐VPA, and H‐VPA but was only partial for IB‐VPA and IA‐VPA. Because of the rapid conversion of the prodrugs to the parent drug, levels of VPA in plasma after administration of the prodrugs peaked at 6–26 min after dosing and did not yield an in vivo sustained‐release dosage profile. Of the five ester prodrugs of VPA, only P‐VPA demonstrated anticonvulsant activity. P‐VPA also was less neurotoxic than VPA and VPD; therefore, it has a better protective index.