Ishizaki T, Chiba K, Manabe K, Koyama E, Hayashi M, Yasuda S, Horai Y, Tomono Y, Yamato C, Toyoki T
Department of Clinical Pharmacology, International Medical Center of Japan, Tokyo.
Clin Pharmacol Ther. 1995 Aug;58(2):155-64. doi: 10.1016/0009-9236(95)90193-0.
To compare the interaction potential of E3810, [(+/-)-sodium 2-[[4-(3-methoxpropoxy)-3-methylpyridin-2-yl]methylsulfinyl] -1H-benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S-mephenytoin 4'-hydroxylation status.
Fifteen healthy male volunteers consisting of six poor metabolizers and nine extensive metabolizers of S-mephenytoin 4'-hydroxylation participated in the study, where two poor and three extensive metabolizers each as a group were randomly allocated to one of the three different treatment sequences with a 3-week washout period among the three trial phases. Each volunteer received an oral once-daily dose of E3810 (20 mg), omeprazole (20 mg), or placebo for 23 days and an intravenous dose (0.1 mg/kg) of diazepam on posttreatment day 8. Plasma concentrations of diazepam and demethyldiazepam were measured up to 16 days after the administration of diazepam.
Diazepam was more slowly metabolized in the poor metabolizers than in the extensive metabolizers. No significant effects of E3810 and omeprazole on any kinetic parameters of diazepam were observed in the poor metabolizers. In the extensive metabolizers, omeprazole significantly decreased the mean clearance of diazepam and increased its half-life, area under the plasma concentration-time curve, and mean residence time compared with E3810 and placebo (p < 0.05 or 0.01), whereas no changes in these kinetic parameters were observed during the treatment with E3810. Omeprazole significantly increased the mean area under the plasma concentration-time curve (0-16 days) of demethyldiazepam in the extensive metabolizers compared with placebo (p < 0.01), whereas E3810 significantly increased it in the poor metabolizers compared with omeprazole or placebo (p < 0.05).
The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole.
比较新型质子泵抑制剂E3810（[(±)-2-[[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚磺酰基]-1H-苯并咪唑钠）和奥美拉唑与地西泮在S-美芬妥英4'-羟化状态方面的相互作用潜力。
15名健康男性志愿者参与了本研究，其中包括6名S-美芬妥英4'-羟化的慢代谢者和9名快代谢者。在三个试验阶段中，每组2名慢代谢者和3名快代谢者被随机分配到三种不同治疗顺序中的一种，各阶段之间有3周的洗脱期。每位志愿者每日口服一次E3810（20毫克）、奥美拉唑（20毫克）或安慰剂，持续23天，并在治疗后第8天静脉注射一剂地西泮（0.1毫克/千克）。在给予地西泮后长达16天的时间内测量地西泮和去甲地西泮的血浆浓度。
地西泮在慢代谢者中的代谢比在快代谢者中更慢。在慢代谢者中未观察到E3810和奥美拉唑对地西泮任何动力学参数有显著影响。在快代谢者中，与E3810和安慰剂相比，奥美拉唑显著降低了地西泮的平均清除率，增加了其半衰期、血浆浓度-时间曲线下面积和平均驻留时间（p<0.05或0.01），而在E3810治疗期间未观察到这些动力学参数有变化。与安慰剂相比，奥美拉唑显著增加了快代谢者中去甲地西泮的血浆浓度-时间曲线下平均面积（0至16天）（p<0.01），而与奥美拉唑或安慰剂相比，E3810在慢代谢者中显著增加了该面积（p<0.05）。
结果表明，作为底物的E3810与S-美芬妥英4'-羟化酶（CYP2C19）的作用较小，与奥美拉唑相比，与地西泮相互作用的潜力（若有的话）要弱得多。
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