title: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition.
abstract: Rosiglitazone and pioglitazone are thiazolidinediones used for treatment of noninsulin-dependent diabetes mellitus. These compounds, along with troglitazone, were evaluated for the ability to induce cytochrome P450 enzymes (P450) in primary human hepatocyte cultures and to inhibit P450 in human microsomes. In induction studies, all three thiazolidinediones caused a dose-dependent increase in CYP3A4 activity and immunoreactive protein. While troglitazone was the most potent, rosiglitazone and pioglitazone generally exceeded troglitazone in absolute CYP3A4 activity achieved at concentrations > or =10 microM. A comparable concentration-dependent increase in CYP2B6 immunoreactive protein was observed with all three thiazolidinediones. Microarray analysis revealed rifampin > troglitazone > pioglitazone > rosiglitazone in terms of CYP3A4 mRNA induction potential with 10 microM compound. Inhibition studies conducted for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, and CYP2E1 showed troglitazone to be the most nonselective and potent inhibitor followed by rosiglitazone and pioglitazone. In vitro, the thiazolidinediones were strong inhibitors of CYP2C8, with K(i) values between 1.7 and 5.6 microM, and of CYP3A4, with K(i) values between 1.6 and 11.8 microM. Troglitazone, in addition, inhibited CYP2C9 (K(i) 0.6 microM). Although the inhibitory effects of the thiazolidinediones have not been demonstrated clinically, our results suggest there is potential for interactions with CYP2C8 substrates. This is the first report of in vitro induction of P450 enzymes by rosiglitazone and pioglitazone. While only the induction of CYP3A4 by troglitazone has been demonstrated in vivo, these results suggest that other thiazolidinediones may have the potential to cause clinically significant drug interactions at sufficiently high doses.
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Jasminder.Sahi@Pfizer.com
authors.forename: Jasminder
authors.initials: J
authors.lastname: Sahi
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Black
authors.forename: Geraldine A
authors.initials: GA
authors.lastname: Hamilton
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.forename: Summer
authors.initials: S
authors.lastname: Jolley
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rose
authors.forename: Darryl
authors.initials: D
authors.lastname: Gilbert
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sinz
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008099:Liver / Q000166:cytology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000032:analysis / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D003577:Cytochrome P-450 Enzyme System; C089946:2,4-thiazolidinedione; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating