Sarich T, Kalhorn T, Magee S, al-Sayegh F, Adams S, Slattery J, Goldstein J, Nelson S, Wright J
Department of Pharmacology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Clin Pharmacol Ther. 1997 Jul;62(1):21-8. doi: 10.1016/S0009-9236(97)90148-X.
Omeprazole, a widely used and potent gastric proton pump inhibitor, induces cytochrome P450 (CYP) 1A2 in humans. Induction is most pronounced in slow metabolizers of S-mephenytoin because CYP2C19 (S-mephenytoin hydroxylase) is responsible for the elimination of omeprazole. Acetaminophen (INN, paracetamol), a widely used and effective analgesic and antipyretic agent, causes serious hepatic and renal toxicity at high doses by conversion of acetaminophen to the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) through CYP1A2, CYP2E1, and CYP3A4. This study evaluated whether omeprazole pretreatment in five rapid and five slow metabolizers of S-mephenytoin could increase thioether (an estimate of NAPQI production) metabolite formation from acetaminophen. The results of this study show that, despite induction of CYP1A2 activity in slow metabolizers (a 75% increase in plasma clearance of caffeine), the formation of NAPQI from acetaminophen was not increased after 7 days of omeprazole administration (40 mg/day). This suggests that induction of CYP1A2 activity by omeprazole is unlikely to increase the risk of acetaminophen hepatotoxicity.
奥美拉唑是一种广泛使用且强效的胃质子泵抑制剂，可诱导人体细胞色素P450（CYP）1A2。这种诱导作用在S-美芬妥因慢代谢者中最为明显，因为CYP2C19（S-美芬妥因羟化酶）负责奥美拉唑的消除。对乙酰氨基酚（国际非专利药品名称，扑热息痛）是一种广泛使用且有效的解热镇痛药，在高剂量时会通过CYP1A2、CYP2E1和CYP3A4将对乙酰氨基酚转化为有毒中间体N-乙酰-p-苯醌亚胺（NAPQI），从而导致严重的肝毒性和肾毒性。本研究评估了在五名S-美芬妥因快速代谢者和五名慢代谢者中进行奥美拉唑预处理是否会增加对乙酰氨基酚硫醚（NAPQI生成的一种估计）代谢产物的形成。本研究结果表明，尽管慢代谢者中CYP1A2活性被诱导（咖啡因血浆清除率增加75%），但在给予奥美拉唑（40毫克/天）7天后，对乙酰氨基酚生成NAPQI的量并未增加。这表明奥美拉唑诱导CYP1A2活性不太可能增加对乙酰氨基酚肝毒性的风险。
