Article révisé par les pairs
Résumé : The metabolism of clocoumarol, a new synthetic vitamin K antagonist by rat liver microsomes, was investigated. A new metabolic route, different from the hydroxylation of the coumarin ring, has been explored. It led to the formation of several metabolites (m1, m2, m3) with an open coumarin cycle. A quantitative and kinetic study of the in vitro formation of the main metabolite (m1) has been performed. An original dosage method of metabolite m1 based on high performance liquid chromatography, has been developed. The optimal conditions for metabolite m1 formation by rat liver microsomes has been determined : 30 min. incubation time, 37 ° C , 13,6 mg of microsomal proteins. A kinetic study, analyzed by Lineweaver-Burk plot, has been performed and the kinetic constants, K(m) and V(max), estimated. The quantitative study indicated that 10% of clocourmarol was metabolized by this new metabolic route. The stimulatory effect of phenobarbital on clocoumarol metabolism has been shown. Treatment of the rats with phenobarbital caused a two-fold increase in metabolite m1 formation. These results indicate that the mixed-function oxidase system of microsomes is involved.