Altered Pharmacokinetics of Sodium Valproate by Simultaneous Administration with Imipenem/Cilastatin Sodium

The plasma sodium valproate (VPA) concentration was significantly lower than the control 0.5, 1, 2 hours after the simultaneous administration of VPA with imipenem/cilastatin (IPM/CS), but the blood cell VPA/plasma VPA concentration was significantly higher at 2 hours after VPA administration. When we injected IPM instead of IPM/CS into rats, the plasma VPA concentration demonstarated similar low levels. The pharmacokinetic parameters of plasma VPA, the volume of distribution (Vd) and clearance (CL) were significantly higher at 1.6 and 1.7 times basal levels white the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve up to 3 hours (AUC0→3) significantly decreased by 0.7 and 0.6 times the basal level after the simultaneous administration of VPA and IPM/CS. The rate of VPA unbound protein was 30.3% before injecting the IPM vein. Although, when IPM was injected inside the vein, it increased by 37.3% at 1 minute and significantly increased by 49.9% at 15 minutes after the administration of IPM. The liver and brain VPA tissue concentration significantly decreased after the simul taneous administration of VPA with IPM/CS.Based on these finding a large amount of unbound type VPA which was produced by competition with a protein binding part of VPA depending on IPM was distributed in the tissue. VPA was especially distributed to blood cells and the kidney. The VPA that had been distributed in the liver later metabolized and was excreted. Therefore, the VPA concentration in plasma, liver and brain was observed to significantly decrease.