Effects of lithium on the pharmacokinetics of valproate in rats

Combined treatment with lithium and valproate has been used for bipolar disorder. However, the studied interaction between these two drugs has not been fully investigated. We therefore examined the effects of lithium on the pharmacokinetics (plasma disappearance, metabolism and urinary excretion) of valproate in rats. Lithium (2 mEq kg(-1)) was administered intraperitoneally twice a day for ten days. Plasma disappearance curves of valproate (50 mg kg(-1), i.v.), valproate-metabolizing activities of UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) in liver microsomes and urinary excretion of free valproate and valproate-glucuronide were examined. The metabolizing activity of UGT and CYP were determined by enzyme assays and a fluorescence polarization immunoassay system. Urinary valproate-glucuronide was obtained using this system by subtracting the free level from total level, which was determined after deconjugating the sample with heat and NaOH. The half-life of plasma disappearance of valproate was 25% reduced by lithium pretreatment (0.428 +/- 0.031 h with repeated lithium pretreatment vs 0.578 +/- 0.062 h for controls). The valproate-metabolizing activity of UGT and CYP were not altered by lithium although lithium increased the urinary excretion of valproate-glucuronide. In conclusion, lithium pretreatment causes a decrease in plasma valproate levels and an increase in urinary excretion of valproate-glucuronide in rats.