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

✍ Scribed by Professor Hsiu-Ying Yu; Mei-Sue Wu; Yu-Zen Shen

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: English
• Weight: 692 KB
• Volume: 14
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510140404

✦ Synopsis

The plasma clearance and metabolicrate characteristics of valproic acid (VPA) were studied using guinea-pigs placed on various (0-08-9pmol ml-'= 11-1303 pg ml-I) steady-state plasma concentrations (CsJ by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 pmol ml-' (88 pg ml-I). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (V-) and the Michaelis-Menten constant (K,) for the primary ( Vmaxl, KmI) and the secondary ( Vmaxz, Kma) pathways were V,,, = 1 -52 pmol min -I kg-I , K,, = 0.15 pmol ml-I , VmaxZ = 24 -98 pmol min-kg -and K,, = 11 a 7 0 pmol ml-l, respectively. The K,, 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 cf,), 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 K , value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the K,, value. These results implied that the primary metabolic parameters may describe the conjugation pathway which is nonlinear within the clinical therapeutic concentration range.