RT Journal Article
SR Electronic
T1 Kinetics of Valproic Acid Glucuronidation: Evidence for in Vivo Autoactivation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1380
OP 1386
DO 10.1124/dmd.107.015719
VO 35
IS 8
A1 Harvey Wong
A1 Vincent Tong
A1 K. Wayne Riggs
A1 Dan W. Rurak
A1 Frank S. Abbott
A1 Sanjeev Kumar
YR 2007
UL http://dmd.aspetjournals.org/content/35/8/1380.abstract
AB 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 (Vmaxapp), the substrate concentration resulting in 50% of Vmaxapp (S50app), and Hill coefficient (n) of 2.10 ± 0.75 μmol/min/kg, 117 ± 56 μM, and 1.34 ± 0.14, respectively. Comparable estimates of Vmaxapp (2.63 ± 0.33 μmol/min/kg), S50app (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. The American Society for Pharmacology and Experimental Therapeutics