H Y Yu1, Y Z Shen. 1. School of Pharmacy, College of Medicine, National Taiwan University Taipei, Republic of China.
Abstract
PURPOSE: Nonlinear conjugation metabolic rate of valproic acid (VPA) has been speculated previously from plasma elimination and liver concentration of VPA in guinea pigs. The purposes of the present study were to assess our speculation by direct measurement of VPA glucuronidation rate in vitro. METHODS: VPA at various concentrations (10-200 micrograms/ml) was incubated with guinea-pig liver-homogenate, mitochondria or microsome in the presence of cofactor, uridine 5'-diphosphoglucuronic acid (UDPGA). The maximum glucuronidation rate (Vmax) and Michaelis-Menten constant (Km) of VPA were determined. RESULTS: On a body weight basis, the Vmax and the Km values of VPA glucuronidation estimated from liver homogenate were 1.8 mumol/min/kg and 0.3 mumol/ml, respectively; and that from microsome suspension were 1.2 mumol/min/kg and 0.16 mumol/ml, respectively. These data are comparable with the primary metabolic parameters observed from previous in vivo study. The glucuronidation clearance calculated from these parameters was 0.10-0.48 fraction of total clearance, which was in agreement with the reported data observed from clinical and animal urinary recoveries of VPA-G. The glucuronidation reaction was not detectable in mitochondria suspension. CONCLUSIONS: The glucuronidation kinetics of VPA is nonlinear and saturable within clinical concentration range. Estimation of in vivo VPA glucuronidation kinetics from in vitro kinetic parameters is feasible.
PURPOSE: Nonlinear conjugation metabolic rate of valproic acid (VPA) has been speculated previously from plasma elimination and liver concentration of VPA in guinea pigs. The purposes of the present study were to assess our speculation by direct measurement of VPA glucuronidation rate in vitro. METHODS:VPA at various concentrations (10-200 micrograms/ml) was incubated with guinea-pig liver-homogenate, mitochondria or microsome in the presence of cofactor, uridine 5'-diphosphoglucuronic acid (UDPGA). The maximum glucuronidation rate (Vmax) and Michaelis-Menten constant (Km) of VPA were determined. RESULTS: On a body weight basis, the Vmax and the Km values of VPA glucuronidation estimated from liver homogenate were 1.8 mumol/min/kg and 0.3 mumol/ml, respectively; and that from microsome suspension were 1.2 mumol/min/kg and 0.16 mumol/ml, respectively. These data are comparable with the primary metabolic parameters observed from previous in vivo study. The glucuronidation clearance calculated from these parameters was 0.10-0.48 fraction of total clearance, which was in agreement with the reported data observed from clinical and animal urinary recoveries of VPA-G. The glucuronidation reaction was not detectable in mitochondria suspension. CONCLUSIONS: The glucuronidation kinetics of VPA is nonlinear and saturable within clinical concentration range. Estimation of in vivo VPA glucuronidation kinetics from in vitro kinetic parameters is feasible.
Authors: R G Dickinson; R C Harland; A M Ilias; R M Rodgers; S N Kaufman; R K Lynn; N Gerber Journal: J Pharmacol Exp Ther Date: 1979-12 Impact factor: 4.030