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Kinetics of Valproic Acid Glucuronidation: Evidence for in Vivo Autoactivation

Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (H.W.), Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey (V.T., S.K.), and Faculty of Pharmaceutical Sciences (K.W.R., F.S.A.) and Child and Family Research Institute, Department of Obstetrics and Gynecology, Faculty of Medicine (D.W.R.), the University of British Columbia, Vancouver, British Columbia, Canada.

Sigmoidal or autoactivation kinetics has been observed in vitro for both cytochrome P450- and UDP-glucuronosyltransferase-catalyzed enzymatic reactions. However, the in vivo relevance of sigmoidal kinetics has never been clearly demonstrated. In the current study we investigate the kinetics of valproic acid glucuronide (VPAG) formation both in vivo in adult sheep and in vitro in sheep liver microsomes (pool of 10). After a 100 mg/kg i.v. bolus dose of valproic acid (VPA) to adult sheep (n = 5), the majority of the dose was recovered in urine as VPAG (79%). Eadie-Hofstee plots of the VPAG formation rate (calculated from urinary excretion rate data for VPAG) were characteristic of autoactivation kinetics and provided estimates of the apparent maximum velocity of an enzymatic reaction (V_max^app), the substrate concentration resulting in 50% of V_max^app (S₅₀^app), and Hill coefficient (n) of 2.10 ± 0.75 µmol/min/kg, 117 ± 56 µM, and 1.34 ± 0.14, respectively. Comparable estimates of V_max^app (2.63 ± 0.33 µmol/min/kg), S₅₀^app (118 ± 53 µM), and n (2.06 ± 0.47) describing overall VPA elimination from plasma were obtained by fitting VPA unbound plasma concentration-time data to a two-compartment model with elimination described by the Hill equation. Consistent with our in vivo observations, Eadie-Hofstee plots of VPAG formation in sheep liver microsomes were characteristic of autoactivation kinetics. To our knowledge, these data provide the first clear demonstration that autoactivation kinetics observed in vitro in liver preparations can translate to the in vivo situation at least under certain experimental conditions and confirm its relevance.

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