The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate.
The goals of the present study were to identify the enzyme responsible for metabolism of itopride hydrochloride (itopride) and to evaluate the likelihood of drug interaction involving itopride. In human liver microsomes, the involvement of flavin-containing monooxygenase in N-oxygenation, the major metabolic pathway of itopride, was indicated by the following results: inhibition by methimazole and thiourea, heat inactivation, and protection against heat inactivation by NADPH. When the effects of ketoconazole on the metabolism of itopride, cisapride, and mosapride citrate (mosapride) were examined using human liver microsomes, ketoconazole strongly inhibited the formation of the primary metabolites of cisapride and mosapride, but not itopride. Other cytochrome P450 (CYP) 3A4 inhibitors, cimetidine, erythromycin, and clarithromycin, also inhibited the metabolism of cisapride and mosapride. In an in vivo study, itopride (30 mg/kg), cisapride (1.5 mg/kg), or mosapride (3 mg/kg) was orally administered to male rats with or without oral pretreatment with ketoconazole (120 mg/kg) twice daily for 2 days. The ketoconazole pretreatment significantly increased the area under the serum concentration curve and the maximum serum concentration of cisapride and mosapride but had no significant effect on the pharmacokinetics of itopride. In addition, itopride did not inhibit five specific CYP-mediated reactions of human liver microsomes. These results suggest that itopride is unlikely to alter the pharmacokinetics of other concomitantly administered drugs.
Mushiroda
T
T
Research & Development Headquarters, Hokuriku Seiyaku Co., Katsuyama, Fukui, Japan. taisei.mushiroda@hokuriku-seiyaku.co.jp
Douya
R
R
Takahara
E
E
Nagata
O
O
D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000378:metabolism* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001549:Benzamides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D001593:Benzyl Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D002927:Cimetidine / Q000494:pharmacology; D020117:Cisapride / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D017291:Clarithromycin / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation / Q000187:drug effects; D004795:Enzyme Stability; D004917:Erythromycin / Q000494:pharmacology; D006358:Hot Temperature; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009025:Morpholines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D010100:Oxygen / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000932:Antiemetics; D001549:Benzamides; D001593:Benzyl Compounds; D007527:Isoenzymes; D009025:Morpholines; D004917:Erythromycin; D002927:Cimetidine; C102254:itopride; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin; C062720:mosapride; D007654:Ketoconazole; D010100:Oxygen; D020117:Cisapride