title: Beta-oxidation of valproate. II. Effects of fasting, glucose, and clofibrate in rats.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle.
authors.forename: K M
authors.initials: KM
authors.lastname: Koch
authors.forename: K S
authors.initials: KS
authors.lastname: Prickett
authors.forename: A W
authors.initials: AW
authors.lastname: Rettenmeier
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
authors.forename: R H
authors.initials: RH
authors.lastname: Levy
mesh_terms: D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D005215:Fasting / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D006706:Homeostasis; D008297:Male; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D014635:Valproic Acid; D002994:Clofibrate; D005947:Glucose