Beta-oxidation of valproate. II. Effects of fasting, glucose, and clofibrate in rats

The effects of glucose infusion, fasting, and clofibrate pretreatment on valproate (VPA) disposition were investigated in rats to determine the role of endogenous fatty acid beta-oxidation in the metabolic formation of 2-en-VPA. Rats undergoing each treatment received a continuous steady-state infusion of VPA and a single intravenous (i.v.) bolus of 2-en-VPA. Elimination clearance of VPA was significantly higher (median 31%, p = 0.002) with glucose infusion as compared with fasting but was unchanged by clofibrate pretreatment as compared with control. Formation clearance of 2-en-VPA was significantly higher with glucose infusion as compared with fasting (median 147%, p = 0.001) and with clofibrate pretreatment as compared with control (median 73%, p = 0.041). Fractional metabolism of VPA by this route averaged 6% in fasted and control rats and 10% in glucose-infused and clofibrate-pretreated rats. Thus, VPA elimination clearance was not greatly influenced by effects on this route in rats. Elimination clearance of 2-en-VPA was also higher with glucose infusion as compared with fasting (median 149%, p = 0.002), and with clofibrate pretreatment as compared with control (median 167%, p less than 0.001). These observations are consistent with glucose-sparing release of endogenous fatty acids (FAs) to compete with VPA for beta-oxidation, and increased beta-oxidative activity after clofibrate treatment. The results of this study provide strong in vivo evidence for involvement of beta-oxidation in metabolism of VPA.