Zhou Li-Ping, Tan Zhi-Rong, Chen Hao, Guo Dong, Chen Yao, Huang Wei-Hua, Wang Lian-Sheng, Zhang Guo-Gang
Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Eur J Clin Pharmacol. 2014 Nov;70(11):1333-8. doi: 10.1007/s00228-014-1724-8. Epub 2014 Sep 17.
Itopride is an effective gastroprokinetic agent mainly used for the treatment of functional dyspepsia. Flavin-containing monooxygenase 3 (FMO3) has been confirmed to be the key enzyme involved in the main itopride metabolic pathway. We investigated whether the FMO3 genotypes can affect itopride metabolism in Chinese healthy volunteers.
Twelve healthy volunteers who had been genotyped for FMO3 gene were selected to participate in our study. Volunteers were given 50 mg itopride orally and then blood samples were collected from 0 to 24 h. The plasma concentrations of itopride and itopride N-oxide were determined by HPLC-MS/MS method.
Itopride and itopride N-oxide both exhibit FMO3 genotype-dependent pharmacokinetic profiles. The area under the plasma concentration-time curve (AUC) of itopride increased by 127.82 ± 41.99 % (P < 0.001) and the AUC of itopride N-oxide decreased by 30.30 ± 25.70 % (P < 0.05) in homozygous FMO3 hhdd subjects (n = 6) compared with the HHDD group (n = 6). The CL/F value was lower in the hhdd group than that in the HHDD group (36.60 ± 7.06 vs. 80.20 ± 15.34 L/h, P < 0.001). But no significant differences in t1/2 value and tmax of itopride and itopride N-oxide were observed between these two genotypes.
The FMO3 allele can significantly affect the metabolism of itopride. The pharmacokinetic parameters of both itopride and itopride N-oxide were significantly different between these two genotypes.
伊托必利是一种有效的促胃肠动力药，主要用于治疗功能性消化不良。含黄素单加氧酶3（FMO3）已被确认为伊托必利主要代谢途径中的关键酶。我们研究了FMO3基因分型是否会影响中国健康志愿者体内伊托必利的代谢。
选取12名已进行FMO3基因分型的健康志愿者参与本研究。志愿者口服50mg伊托必利，然后在0至24小时内采集血样。采用高效液相色谱-串联质谱法测定伊托必利及其N-氧化物的血浆浓度。
伊托必利及其N-氧化物均呈现出FMO3基因型依赖性药代动力学特征。与HHDD组（n = 6）相比，纯合FMO3 hhdd组（n = 6）中伊托必利的血浆浓度-时间曲线下面积（AUC）增加了127.82±41.99%（P < 0.001），伊托必利N-氧化物的AUC降低了30.30±25.70%（P < 0.05）。hhdd组的CL/F值低于HHDD组（36.60±7.06 vs. 80.20±15.34 L/h，P < 0.001）。但在这两种基因型之间，未观察到伊托必利及其N-氧化物的t1/2值和tmax有显著差异。
FMO3等位基因可显著影响伊托必利的代谢。这两种基因型之间，伊托必利及其N-氧化物的药代动力学参数均存在显著差异。
