Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits

Purpose. We investigated the effect of meropenem (MEPM) on the disposition kinetics of valproate (VPA) and its metabolites in rabbits. Methods. Rabbits were given 75 mg/kg VPA intravenously with or without 300 mg/kg MEPM. Results. The plamsa total clearance of VPA was significantly increased to a bout 1.5 times the control (6.09 mL/min/kg vs. 4.28 mL/min/kg) by MEPM (P<0 .05). The values of the area under the plasma concentration-time curve (AUC ) of 2-en-VPA, a product of P-oxidation, and VPA-glucuronide (VPA-G) were s ignificantly decreased to about 55% and 78% of the control, respectively (P <0.05). The cumulative urinary excretions of VPA in the control and MEPM-tr eated groups were 0.54% and 0.62% of the dose, respectively, whereas those of VPA-G were 45.6% and 62.5%, respectively. The urinary excretion of VPA-G was significantly increased by MEPM (P<0.05). Further, in the case of 33.8 mg/kg VPA-G administered intravenously the AUC value of VPA-G was unchange d by MEPM, whereas that of the generated VPA was significantly decreased to about half of the control. Conclusions. The increase of the total clearance of VPA caused by MEPM appe ars to be a consequence of increased renal clearance of VPA-G, as well as s uppression of VPA-G hydrolysis in the liver.