药物分析学报

抽象的

Atypical Kinetics of Valproic Acid Glucuronidation In vitro and In vivo in Humans

Harvey Wong, Binfeng Xia, Vincent Tong, Sanjeev Kumar and Jane R Kenny

Atypical kinetics has been observed in vitro for both cytochrome P450 and UDP-glucuronosyltransferase catalyzed enzymatic reactions. The in vitro and in vivo kinetics of valproic acid- glucuronide (VPA-glucuronide) formation was investigated in humans.
VPA-glucuronide formation kinetics was investigated in vitro using human cryoperserved hepatocytes (pool of 10). Estimates of Vmax app (39.5 ± 3.3 pmol/min/106 cells), S50 app (224 ± 34 µM) and n (2.34 ± 0.28) was obtained by fitting VPA-glucuronide formation rate vs VPA incubation concentration data to the Hill equation. In vitro EadieHofstee plots were “hooked” and characteristic of atypical sigmoidal/autoactivation kinetics.
In vivo Eadie-Hofstee plots of VPA-glucuronide formation rate (calculated from urinary excretion rate data for VPA-glucuronide) were constructed using data from four human subjects given a 1000 mg VPA oral dose [1]. The positive slope of linear regression lines for these plots was consistent with in vivo atypical sigmoidal/autoactivation kinetics.
In summary, these data build upon our previous observations in sheep and provide the first demonstration that VPA-glucuronide formation exhibits atypical kinetics in vitro in human hepatocytes. Available in vivo data is consistent with in vitro results suggesting that VPA-glucuronidation exhibits atypical sigmoidal/autoactivation kinetics in vivo in humans.