Oxatomide is an
antiallergic drug used for the treatment of diseases mediated by type I
allergy. Recently,
terfenadine and
astemizole, which have
antiallergic actions similar to those of
oxatomide, showed side effects on the cardiovascular system. This might be because concomitant drugs such as
itraconazole inhibit
cytochrome P450 3A4 (
CYP3A4), the
enzyme responsible for the degradation of
terfenadine and
astemizole, and thus the blood concentrations of the drugs are abnormally increased. In another article of this issue, we have reported that
oxatomide is metabolized by CYP2D6-Val and
CYP3A4, and simultaneously inhibits the metabolism of the model substrates for these
enzymes. In this study, we performed the kinetic analysis of
oxatomide metabolism using microsomes prepared from human liver, and found that the Km and Vmax values were 26.1 microM and 1254.4 pmol/mg
protein/min, respectively.
Ketoconazole, one of the representative inhibitors for
CYP3A4, potently inhibited the metabolism of
oxatomide, but other well-known CYP inhibitors did not show significant inhibition. These results suggest that the metabolism of
oxatomide is principally catalyzed by
CYP3A4. Furthermore,
oxatomide inhibited the metabolism of (+/-)
bufuralol and
testosterone, model substrates for
CYP2D6 and
CYP3A4, respectively, in a dose-dependent manner with the Ki values of 57.4 and 24.3 microM, respectively. These observations, together with the finding that the putative highest concentration of
oxatomide in blood was congruent with 40 ng/ml ( congruent with 93 nM) at 4 h after each dosage during consecutive 6-d administration, encouraged us to conclude that
oxatomide won't inhibit
CYP2D6 or
CYP3A4 at clinical doses.