DISPOSITION OF VALPROMIDE, VALPROIC ACID, AND VALNOCTAMIDE IN THE BRAIN, LIVER, PLASMA, AND URINE OF RATS

Valpromide (VPD) and valnoctamide (VCD) are amide derivatives of valpr oic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent models, both VPD and VCD are more potent as anticonvulsants than VPA. However, in humans, VPD serves as a prodrug to VPA, whereas VCD acts as a drug on its own, which is not biotransformed to its corresponding acid-valnoctic acid (VCA). The present study investigates the pharmac okinetics (PKs) of VPD and VCD in rats by monitoring the levels of the se two amide isomers in the brain, liver, plasma, and urine of rats, T he disposition of VPD and VCD was analyzed in a comparative manner wit h that of VPA, The following PK parameters were obtained for VPD and V CD, respectively: clearance, 6.1 and 3 ml/min/kg; volume of distributi on (V-ss), 0.63 and 0.58 liter/kg; half-life (t(1/2)), 42 and 94 min; and mean residence time (MRT), 102 and 196 min. The clearance of VCD i n rats was half of that of VPD, and their V-ss was similar, Therefore, VCD, t(1/2), and MRT were twice as long as those of VPD, PK analysis of VPD and VCD liver and brain levels gave similar major PK parameters to those obtained from the plasma data, VPD underwent hepatic biotran sformation to VPA, which persisted in the liver and brain for a longer period than VPD, The fraction metabolized of VPD to VPA was 42%, The brain was not found to be a metabolic site of the VPD-VPA biotransform ation, Unlike VPD, VCD did not undergo amide-acid biotransformation to its corresponding acid, but was eliminated by biotransformation to un identified metabolites. In contrast to VPD and VCD that distributed ab out evenly between the plasma, liver, and brain, VPA showed different disposition patterns in the plasma, liver, and brain, VCD and VPD dist ribute better into the brain than VPA, a fact that may contribute to t heir better anticonvulsant activity.