title: Metabolism and transporter-mediated drug-drug interactions of the endothelin-A receptor antagonist CI-1034.
abstract: 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.
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. Jasminders@cellzdirect.com
authors.forename: Jasminder
authors.initials: J
authors.lastname: Sahi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sinz
authors.forename: Scott
authors.initials: S
authors.lastname: Campbell
authors.forename: Rouchelle
authors.initials: R
authors.lastname: Mireles
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rose
authors.forename: Shamsi
authors.initials: S
authors.lastname: Raeissi
authors.forename: Muhammed F
authors.initials: MF
authors.lastname: Hashim
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Ye
authors.forename: Sonia M
authors.initials: SM
authors.lastname: de Morais
authors.forename: Christopher
authors.initials: C
authors.lastname: Black
authors.forename: Meera
authors.initials: M
authors.lastname: Tugnait
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Keller
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004311:Double-Blind Method; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D010919:Placebos; D012333:RNA, Messenger / Q000235:genetics; D013843:Thiazines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D004791:Enzyme Inhibitors; D027361:Organic Anion Transporters; C419982:PD 180988; D010919:Placebos; D012333:RNA, Messenger; D013843:Thiazines; D003577:Cytochrome P-450 Enzyme System