Sahi Jasminder, Sinz Michael W, Campbell Scott, Mireles Rouchelle, Zheng Xianxian, Rose Kelly A, Raeissi Shamsi, Hashim Muhammed F, Ye Yuyang, de Morais Sonia M, Black Christopher, Tugnait Meera, Keller Laurence H
Department of Pharmacokinetics Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
Chem Biol Interact. 2006 Feb 1;159(2):156-68. doi: 10.1016/j.cbi.2005.11.001. Epub 2005 Dec 13.
CI-1034, an endothelin-A receptor antagonist was being developed for pulmonary hypertension. Drug-drug interaction studies using human hepatic microsomes were conducted to assess CYP1A2, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 inhibition potential; CYP3A4 induction potential was evaluated using primary human hepatocytes. CI-1034 moderately inhibited CYP2C9 (IC(50) 39.6 microM) and CYP3A4 activity (IC(50) 21.6 microM); CYP3A4 inhibition was metabolism-dependent. In human hepatocytes, no increase in CYP3A4 activity was observed in vitro, while mRNA was induced 15-fold, similar to rifampin, indicating that CI-1034 is both an inhibitor and inducer of CYP3A4. A 2-week clinical study was conducted to assess pharmacokinetics, pharmacodynamics and safety. No significant changes were observed in [formula: see text] between days 1 and 14. However, reversible elevations of serum liver enzymes were observed with a 50mg BID dose and the program was terminated. To further understand the interactions of CI-1034 in the liver and possible mechanisms of the observed hepatotoxicity, we evaluated the effect of CI-1034 on bile acid transport and previously reported that CI-1034 inhibited biliary efflux of taurocholate by 60%, in vitro. This indicated that inhibition of major hepatic transporters could be involved in the observed hepatotoxicity. We next evaluated the in vitro inhibition potential of CI-1034 with the major hepatic transporters OATP1B1, OATP1B3, OATP2B1, MDR1, MRP2 and OCT. CI-1034 inhibited OATP1B1 (K(i) 2 microM), OATP1B3 (K(i) 1.8 microM) and OATP2B1 activity (K(i) 3.3 microM) but not OCT, MDR1 or MRP2 mediated transport. Our data indicates that CI-1034 is an inhibitor of major hepatic transporters and inhibition of bile efflux may have contributed to the observed clinical hepatotoxicity. We recommend that in vitro drug-drug interaction panels include inhibition and induction studies with transporters and drug metabolizing enzymes, to more completely assess potential in vivo interactions or toxicity.
CI-1034是一种内皮素A受体拮抗剂，正被开发用于治疗肺动脉高压。利用人肝微粒体进行了药物相互作用研究，以评估其对CYP1A2、CYP2C9、CYP2C19、CYP3A4和CYP2D6的抑制潜力；使用原代人肝细胞评估CYP3A4的诱导潜力。CI-1034中度抑制CYP2C9（IC50为39.6微摩尔）和CYP3A4活性（IC50为21.6微摩尔）；CYP3A4的抑制作用依赖于代谢。在人肝细胞中，体外未观察到CYP3A4活性增加，而mRNA诱导了15倍，与利福平相似，表明CI-1034既是CYP3A4的抑制剂也是诱导剂。进行了一项为期2周的临床研究，以评估其药代动力学、药效学和安全性。在第1天和第14天之间，[公式：见原文]未观察到显著变化。然而，50mg每日两次的剂量观察到血清肝酶可逆性升高，该项目因此终止。为了进一步了解CI-1034在肝脏中的相互作用以及观察到的肝毒性的可能机制，我们评估了CI-1034对胆汁酸转运的影响，此前报道CI-1034在体外可抑制牛磺胆酸盐的胆汁外排60%。这表明主要肝转运体的抑制可能与观察到的肝毒性有关。接下来，我们评估了CI-1034对主要肝转运体OATP1B1、OATP1B3、OATP2B1、MDR1、MRP2和OCT的体外抑制潜力。CI-1034抑制OATP1B1（K(i)为2微摩尔）、OATP1B3（K(i)为1.8微摩尔）和OATP2B1活性（K(i)为3.3微摩尔），但不抑制OCT、MDR1或MRP2介导的转运。我们的数据表明CI-1034是主要肝转运体的抑制剂，胆汁外排的抑制可能导致了观察到的临床肝毒性。我们建议体外药物相互作用研究小组应包括对转运体和药物代谢酶的抑制和诱导研究，以更全面地评估潜在的体内相互作用或毒性。
