Impact of Intestinal CYP2C19 Genotypes on the Interaction between Tacrolimus and Omeprazole, but Not Lansoprazole, in Adult Living-Donor Liver Transplant Patients
Impact of Intestinal CYP2C19 Genotypes on the Interaction between Tacrolimus and Omeprazole, but Not Lansoprazole, in Adult Living-Donor Liver Transplant Patients
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DOI：
10.1124/dmd.108.025833
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发表时间：
2009-04-01
影响因子：
3.9
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
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作者：
Hosohata, Keiko;Masuda, Satohiro;Inui, Ken-ichi
为了评估肠细胞色素P450 2C 19对他克莫司和质子泵抑制剂之间相互作用的影响，我们检查了89例成人活体肝移植患者在术后第22 - 28天与奥美拉唑（20 mg）或兰索拉唑（30 mg）联合给药的他克莫司浓度/剂量比[（ng/ml）/（mg/天）]，分别考虑天然肠和移植肝的CYP 2C 19基因型。他克莫司与奥美拉唑联合给药的浓度/剂量比在有两种变异的患者中显著更高（*2或 *3）对于肠道CYP 2C 19（中位数，6.38;范围，1.55-22.9）比肠野生型纯合子（中位数，2.11;范围，1.04-2.54）和杂合子（中位数，2.11;范围，0.52-4.33）（P = 0.010），但增加的程度通过在移植肝中携带野生型等位基因而减弱，即使患者是CYP 3A 5 *1非携带者。相反，在天然肠道和移植肝脏中的CYP 2C 19多态性对他克莫司和兰索拉唑之间的相互作用几乎没有影响，但CYP 3A 5 *1非携带者显示出比CYP 3A 5 *1携带者更高的他克莫司浓度/剂量比。此外，我们的体外实验显示，兰索拉唑对CYP 3A 5介导的他克莫司代谢的抑制作用强于奥美拉唑，尽管不显著（兰索拉唑的IC 50 = 19.9 +/- 13.8 μ M，奥美拉唑的IC 50 = 53.7 +/- 6.1 μ M）。我们的研究结果表明，肠道和移植肝CYP 2C 19在奥美拉唑代谢中的作用相对大于兰索拉唑，因此CYP 3A 5对他克莫司代谢的影响可能被与CYP 2C 19基因型相关的奥美拉唑相互作用掩盖。
To assess the effects of intestinal cytochrome P450 2C19 on the interaction between tacrolimus and proton pump inhibitors, we examined the concentration/dose ratio [(ng/ml)/(mg/day)] of tacrolimus coadministered with omeprazole (20 mg) or lansoprazole (30 mg) to 89 adult living-donor liver transplant patients on postoperative days 22 to 28, considering the CYP2C19 genotypes of the native intestine and the graft liver, separately. The concentration/dose ratio of tacrolimus coadministered with omeprazole was significantly higher in patients with two variants (*2 or *3) for intestinal CYP2C19 (median, 6.38; range, 1.55-22.9) than intestinal wild-type homozygotes (median, 2.11; range, 1.04-2.54) and heterozygotes (median, 2.11; range, 0.52-4.33) (P = 0.010), but the extent of the increase was attenuated by carrying the wild-type allele in the graft liver even when patients were CYP3A5*1 noncarriers. Conversely, the CYP2C19 polymorphisms both in the native intestine and in the graft liver little influenced the interaction between tacrolimus and lansoprazole, but CYP3A5*1 noncarriers showed higher tacrolimus concentration/dose ratio than CYP3A5*1 carriers. Furthermore, our experiments in vitro revealed that lansoprazole had a stronger inhibitory effect on the CYP3A5-mediated metabolism of tacrolimus than omeprazole, although not significantly (IC50 = 19.9 +/- 13.8 mu M for lansoprazole, 53.7 +/- 6.1 mu M for omeprazole). Our findings suggest that intestinal and graft liver CYP2C19 plays a relatively greater role in the metabolism of omeprazole than it does for lansoprazole, so that the effects of CYP3A5 on the metabolism of tacrolimus might be masked by the interaction with omeprazole associated with the CYP2C19 genotype.