Masubuchi N, Li A P, Okazaki O
Drug Metabolism and Analytical Chemistry Research Laboratory, Daiichi Pharmaceutical, Tokyo, Japan.
Chem Biol Interact. 1998 Jul 3;114(1-2):1-13. doi: 10.1016/s0009-2797(98)00031-3.
Primary human hepatocytes contain a full complement of human drug-metabolizing enzymes and therefore represent a relevant experimental system for the evaluation of pharmacokinetic drug-drug interaction potential in human. In this study, the cytochrome P450 (CYP) induction potential of pantoprazole (PAN) was evaluated and compared to two other proton pump inhibitors (PPIs), omeprazole (OM) and lansoprazole (LAN). Primary human hepatocytes from three donors were studied. The hepatocytes were cultured for 3 days, followed by treatment for 3 days with the PPIs at 2, 5 and 10 microM. Two other known CYP inducers, 3-methylcholanthrene at 1 microM and rifampin at 50 microM, were also evaluated. Induction potentials of these chemicals for CYP1A and CYP3A were evaluated by isozyme activity and isozyme content. 7-Ethoxyresorufin-O-deethylase and testosterone 6beta-hydroxylase activities were used as endpoints for CYP1A and CYP3A, respectively. Isozyme protein contents of CYP1A and CYP3A were evaluated via Western blotting. The results showed that for CYP1A induction, the rank ordering in induction potential was consistently OM > LAN > PAN. CYP3A induction by the PPI's were observed in two of the three hepatocyte cultures, with no apparent differences in induction potency for the three compounds. Our results on CYP1A induction suggest that PAN has a lower drug-drug interaction potential than OM and LAN.
原代人肝细胞含有完整的人类药物代谢酶，因此是评估人类药代动力学药物 - 药物相互作用潜力的相关实验系统。在本研究中，评估了泮托拉唑（PAN）的细胞色素P450（CYP）诱导潜力，并与另外两种质子泵抑制剂（PPI）奥美拉唑（OM）和兰索拉唑（LAN）进行了比较。研究了来自三名供体的原代人肝细胞。将肝细胞培养3天，然后用2、5和10微摩尔的PPI处理3天。还评估了另外两种已知的CYP诱导剂，1微摩尔的3 - 甲基胆蒽和50微摩尔的利福平。通过同工酶活性和同工酶含量评估这些化学物质对CYP1A和CYP3A的诱导潜力。分别使用7 - 乙氧基试卤灵 - O - 脱乙基酶和睾酮6β - 羟化酶活性作为CYP1A和CYP3A的终点。通过蛋白质印迹法评估CYP1A和CYP3A的同工酶蛋白含量。结果表明，对于CYP1A诱导，诱导潜力的排序始终是OM > LAN > PAN。在三种肝细胞培养物中的两种中观察到PPI对CYP3A的诱导，三种化合物的诱导效力没有明显差异。我们关于CYP1A诱导的结果表明，PAN的药物 - 药物相互作用潜力低于OM和LAN。
