Identification of human p450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its inhibitory effect on enzyme activity.
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.
Goto
Akihisa
A
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Adachi
Yasuhisa
Y
Inaba
Atsuhiro
A
Nakajima
Hiroshi
H
Kobayashi
Hiroyuki
H
Sakai
Kenichi
K
D018926:Anti-Allergic Agents / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology
D018926:Anti-Allergic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010879:Piperazines; D019363:Cytochrome P-450 CYP1A1; C015408:oxatomide