Oxatomide is an
antiallergic drug used for the treatment of diseases mediated by type I
allergy. Recently, it has been reported that
terfenadine and
astemizole, which have
antiallergic actions similar to those of
oxatomide, show side effects on the cardiovascular system, such as QT prolongation, ventricular
arrhythmia and
cardiac arrest. This might be because concomitant drugs such as
itraconazole inhibit
cytochrome P450 3A4 (
CYP3A4), the
enzyme responsible for degradation of
terfenadine and
astemizole, and thus the blood concentrations of the drugs are abnormally increased. On the other hand,
isoforms of P450 involved in the metabolism of
oxatomide have not been clarified. Therefore, we attempted to identify these
isoforms using microsome preparations of in vitro expression systems derived from a human lymphoblastoid cell line.
Oxatomide was metabolized by CYP2D6-Val and
CYP3A4, but not by
CYP1A2, CYP2C9-Arg, CYP2C9-Cys or
CYP2C19. We also examined whether
oxatomide showed inhibitory effects on metabolic activity of individual P450
isozymes using model substrates for each
isozyme.
Oxatomide did not inhibit the metabolism of the model substrates for
CYP1A2, CYP2C9-Arg, CYP2C9-Cys and
CYP2C19, but inhibited the degradation of those for CYP2D6-Val and
CYP3A4. It was found that
oxatomide is metabolized by
CYP2D6 and
CYP3A4 in human liver microsomes, and simultaneously acts as an inhibitor for these
isoforms, responsible for the metabolism of the
drug itself.