Effects Of Methimazole On Itopride Pharmacokinetics And Its Relationship With FMO3 Polymorphism In Vivo

AIMS: The present study was to determine the effect of methimazole on pharmacokinetics of itopride, a substrate of FM03 in vivo related to different FMO3 genotype groupsMETHODS: A total of 504 male healthy Chinese volunteers were genotyped in FMO₃ using the PCR-RFLP assay. Fifteen unrelated healthy male volunteers with different FMO3 genotypes (eight FM03*W/*W, seven FMO3*L/*L) were selected to participate in this study. A 2-phase opened randomized parallel study was designed. Itopride hydrochloride tablets (50mg orally) pharmacokinetics with and without coadminis-tration of methimazole (20mg orally) were measured for up to 36h by liquid chromatography-mass spectrometry in a two-phase randomized control study.RESULTS: The frequencies of FMO3 E158K,E308G and N61K are 19.1%,19.8% and 0.8%. respectively. The allele frequencies were in Hardy-Weinberg equilibrium. FMO3 E158K and E308G were proved linkage.Coadministration of methimazole obviously increased the AUC_0-36hof itopride (1020.17±98.91ng.h / ml vs 1547.28±146.57 ng.h/ml, P=0.004) and AUC_0-∞,( 1064.49±107.22ng.h / ml vs 51577.56±151.91ng.h/ml, P=0.005) and significantly increased Cmax of itopride (272.23±33.23ng/ml vs500.28±76.23ng/ml,P=0.023) and tl/2(1.52±0.09h vs 4.79±0.42h,P=0.000).And the extent of FMO3 inhibition is correlated with E158K and E308G genotypes.CONCLUSIONS: In vivo, methimazole can produce significant changes in the pharmacokinetics of itopride; taking normal dose methimazole can inhibit FMO3 activity significantly. This result is in corresponding with the result in vitro. So more attention should be paid when methimazole was used in combination with drugs that aresubstrates of FMO3. And the extent of FMO3 inhibition is not correlated with FMO3 E158K and E308G genotypes significantly.