Nonlinear elimination and hepatic concentration of conjugation‐ metabolite of valproate in guinea‐pigs

Abstract

The plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea-pigs placed on various (0.08-9 mumol ml-1 = 11-1303 micrograms ml-1) steady-state plasma concentrations (Css) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 mumol ml-1 (88 micrograms ml-1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (Vmax) and the Michaelis-Menten constant (Km) for the primary (Vmax1, Km1) and the secondary (Vmax2, Km2) pathways were Vmax1 = 1.52 mumol min-1 kg-1, Km1 = 0.15 mumol ml-1, Vmax2 = 24.98 mumol min-1 kg-1 and Km2 = 11.70 mumol ml-1, respectively. The Km1 value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose-dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (fu), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The Km value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the Km1 value.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

“…After the intravenous administration of VPA, its AUC0-4 h (303 mg h ml ) was similar to the reported values, 225 mg h ml -1 (Yu et al, 1993) and 330 mg h ml -1 (Dickinson et al, 1979), at the same intravenous dose. The formation of toxic metabolites, 4-VPA and 2,4-VPA were rapid; they were detected in the plasma from the second blood sampling time point (10 min).…”

“…VPA is metabolized to 4-VPA via microsomal cytochrome P450-mediated dehydrogenation and 4-ene-VPA is further bioactivated through mitochondrial b-oxidation to 2,4-diene-VPA (Tang and Abbott, 1997). The decreased plasma exposure of 4-VPA seems to be due to the saturation of microsomal cytochrome P450 and liver distribution (Brouwer et al, 1993;Yu et al, 1993).…”

Concentration-dependent disposition of glucuronide metabolite of valproate

“…It obeys Michaelis-Menten type kinetics Yu & Shen 1996), with the Michaelis-Menten constant (K m ) in the middle of the therapeutic concentration range (Yu & Shen 1996), and the maximum biotrans-formation rate (V max ) approximating a high therapeutic dosing rate . Non-linear biliary excretion (Dickinson et al 1979;Yu et al 1993) and urinary recovery (Granneman et al 1984b) of VPAG have been reported. Biliary VPA is equivalent to, but biliary VPAG decreases relative to, the liver concentration of VPA .…”