Interaction of the anticonvulsants, denzimol and nafimidone, with liver cytochrome P450 in the rat

The presence of an imidazole moiety in the chemical structure of denzimol and nafimidone suggested that these new anticonvulsants might interfere with cytochrome P450-mediated mixed function monooxygenase activities. We therefore investigated their ability to bind reversibly to rat liver Cytochrome P450. Both drugs displayed a type II spectra. The Ks values of binding were 6.66 and 7.00 mM, respectively, for denzimol and nafimidone. In other in-vitro studies the IC50 of the inhibition caused by denzimol and nafimidone was determined on carbamazepine (CBZ) epoxidation and diazepam C3-hydroxylation and N1-dealkylation. The IC50 values for CBZ epoxidation were 4.46 x 10(-7) and 2.95 x 10(-7) M, respectively, in the presence of denzimol and nafimidone. The IC50 values for diazepam C3-hydroxylation were 1.44 x 10(-6) and 1.00 x 10(-6) M, respectively, and those for N1-dealkylation 6.66 x 10(-7) and 5.95 x 10(-7) M. The inhibition of CBZ metabolism was also investigated ex-vivo and in-vivo after single oral doses (15 and/or 60 mg kg-1) of denzimol or nafimidone. Inhibition of CBZ-10,11-epoxidation by the two drugs was time- and dose-dependent. Further studies in-vivo showed that denzimol and nafimidone prolong pentobarbitone sleeping times indicating that both drugs bind to rat liver microsomes and are potent inhibitors in the rat of mixed function monooxygense activities both in-vitro and in-vivo.