Abstract

Previously, a significant decrease in the trough plasma-concentration of valproic acid (VPA) owing to the concomitant administration of panipenem (PAPM)/betamipron, a carbapenem antibiotic, in epileptic patients was reported. To determine the site and mechanism of the drug interaction between VPA and PAPM, we performed in vivo and in vitro experiments using rats. A 30 mg/kg bolus dose of VPA was given i.v. to normal Sprague-Dawley rats, nephrectomized rats, and hepatectomized rats, with and without prior treatment of PAPM. PAPM treatment resulted in a significant reduction of biological half-life and a significant increase of total body clearance in normal rats. The effects of PAPM on the disposition kinetics of VPA were also observed in nephrectomized rats, whereas hepatectomy abolished the interaction completely. Thus, the site of interaction was identified as the liver. At steady state, PAPM treatment significantly increased total body clearance, the biliary excretion rate of VPA glucuronide, and the apparent metabolic clearance of VPA by glucuronidation, but did not affect the biliary excretion clearance of VPA glucuronide. Initial uptake velocity of VPA into rat hepatocytes proportionally increased as a function of VPA concentration added and was not affected by PAPM. The plasma-unbound fraction of VPA in vitro was not altered by PAPM. These data demonstrate that PAPM does not affect the uptake of VPA into the liver, the plasma-unbound fraction, and the excretion process of VPA glucuronide. Consequently, PAPM appears to enhance the rate of metabolism of VPA to VPA glucuronide in the liver.