There is evidence indicating that the
carbapenem antibiotic panipenem decreases plasma concentrations of
valproic acid (VPA) in epileptic patients during VPA
therapy. The mechanism for
panipenem-induced changes in the pharmacokinetics of VPA was investigated in rats with and without bile duct cannulation. The effect of
panipenem on the pharmacokinetics of
diclofenac, which undergoes extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of
body weight) or
diclofenac (10 mg/kg of
body weight) was administered intravenously under the steady-state plasma
panipenem concentration of 4 microgram/ml, which had been achieved by a constant infusion rate.
Panipenem decreased the plasma VPA concentrations in rats without bile duct cannulation but did not change the volume of the initial space and protein binding of VPA. However,
panipenem had no effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in plasma
diclofenac concentration observed in the absence of
panipenem was diminished in the presence of
panipenem. These findings suggest that
panipenem decreases plasma VPA concentrations by suppressing its enterohepatic recirculation, probably due to a
panipenem-induced decrease in the numbers of enteric bacteria.