SCHOOL OF MEDICINE

Department of Medicine

Clinical Pharmacology

2C9 REFERENCES

 2C9 SUBSTRATES: 

AMITRIPTYLINE
Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. [ PMID 9663807 ]
Miners JO, Birkett DJ.
Br J Clin Pharmacol 1998 Jun;45(6):525-38.

CELECOXIB
Cytochrome P450 2C9 Variants Influence Response to Celecoxib for Prevention of Colorectal Adenoma. [ PMID 19233181 ]
Chan AT, Zauber AG, Hsu M, Breazna A, Hunter DJ, Rosenstein RB, Eagle CJ, Hawk ET, Bertagnolli MM.
Gastroenterology. 2009 Feb 21.

Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. [ PMID 17681167 ]
Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, Niro V, Andriulli A, Leandro G, Di Mario F, Dallapiccola B.
Gastroenterology. 2007 Aug;133(2):465-71.

NOT CANDESARTAN
Candesartan cilexetil: a review of its preclinical pharmacology. [ PMID 9330999 ]
Nishikawa K, Naka T, Chatani F, Yoshimura Y.
J Hum Hypertens 1997 Sep;11 Suppl 2:S9-S17.

Pharmacokinetic drug interaction studies with candesartan cilexetil. [ PMID 9331003 ]
Jonkman JH, van Lier JJ, van Heiningen PN, Lins R, Sennewald R, Hogemann A.
J Hum Hypertens 1997 Sep;11 Suppl 2:S31-S35.

Absorption, metabolism and excretion of 14C-candesartan and 14C-candesartan cilexetil in healthy volunteers. [ PMID 9331001 ]
van Lier JJ, van Heiningen PN, Sunzel M.
J Hum Hypertens 1997 Sep;11 Suppl 2:S27-S28.

DICLOFENAC
In vivo inhibition profile of cytochrome P450tb (CYP2C9) by (±)-fluvastatin. [ PMID 7586933 ]
Transon C, Leemann T, Vogt N, Dayer P.
Clin Pharmacol Ther 1995;58(4):412-417.

FENOFIBRATE
Fenofibrate potentiates warfarin effects. [ PMID 12549950 ]
Kim KY, Mancano MA.
Ann Pharmacother. 2003 Feb;37(2):212-5.

FLUOXETINE
Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. [ PMID 9663807 ]
Miners JO, Birkett DJ.
BrJ Clin Pharmacol 1998 Jun;45(6):525-38

FLUVASTATIN
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. [ PMID 10064574 ]
Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, Robinson WT.
Drug Metab Dispos 1999 Mar;27(3):410-6

GLIMEPIRIDE
Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes. [ PMID 16325295 ]
Suzuki K, Yanagawa T, Shibasaki T, Kaniwa N, Hasegawa R, Tohkin M.
Diabetes Res Clin Pract. 2006 May;72(2):148-54.

Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. [ PMID 12235454 ]
Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivistö KT.
Clin Pharmacol Ther. 2002 Sep;72(3):326-32.

GLIPIZIDE
Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide. [ PMID 11406737 ]
Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivistö KT.
Clin Pharmacol Ther. 2001 Jun;69(6):400-6.

Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. [ PMID 10208645 ]
Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT.
Pharmacogenetics. 1999 Feb;9(1):71-80.

GLYBURIDE
Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. [ PMID 11956512 ]
Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, Roots I.
Clin Pharmacol Ther 2002 Apr;71(4):286-96.

GLIBENCLAMIDE
Effects of clarithromycin and grapefruit juice on the pharmacokinetics of glibenclamide. [ PMID 17223855 ]
Lilja JJ, Niemi M, Fredrikson H, Neuvonen PJ.
Br J Clin Pharmacol. 2007 Jun;63(6):732-40.

Impact of cytochrome P450 CYP2C9 variant allele CYP2C9*3 on the pharmacokinetics of glibenclamide and lornoxicam in Chinese subjects. [ PMID 16342679 ]
Zhang YF, Chen XY, Guo YJ, Si DY, Zhou H, Zhong DF.
Yao Xue Xue Bao. 2005 Sep;40(9):796-9.

IBUPROFEN
Stereo- and nonstereospecific oxidation by P450tb (CYP2C): The major elimination pathway of (+/-) -ibuprofen. [ PMID 1462152 ]
Leeman, T., Bonnabry, P., and Dayer, P.
Clin Pharmacol Ther 55:208, 1994.

IRBESARTAN
CYP2C9 Ile359Leu polymorphism, plasma irbesartan concentration and acute blood pressure reductions in response to irbesartan treatment in Chinese hypertensive patients. [ PMID 16541193 ]
Chen G, Jiang S, Mao G, Zhang S, Hong X, Tang G, Li Z, Liu X, Zhang Y, Xing H, Wang B, Yu Y, Xu X.
Methods Find Exp Clin Pharmacol. 2006 Jan-Feb;28(1):19-24.

Determinants of steady-state torasemide pharmacokinetics: impact of pharmacogenetic factors, gender and angiotensin II receptor blockers. [ PMID 18399713 ]
Werner D, Werner U, Meybaum A, Schmidt B, Umbreen S, Grosch A, Lestin HG, Graf B, Zolk O, Fromm MF.
Clin Pharmacokinet. 2008;47(5):323-32.

LORNOXICAM
Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in human. [ PMID 15764711 ]
Guo Y, Zhang Y, Wang Y, Chen X, Si D, Zhong D, Fawcett JP, Zhou H.
Drug Metab Dispos. 2005 Jun;33(6):749-53.

LORSARTAN
A mutation in CYP2C9 is responsible for decreased metabolism of losartan. [ PMID 10096267 ]
Spielberg S, McCrea J, Cribb A, Rushmore T, Waldman SA. Bjornnson T, Lo M-W, Goldberg M.
Clin Pharmacol Ther. 1999 Mar;65(3):348-52.

MELOXICAM
Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4. [ PMID 9493314 ]
Chesné C, Guyomard C, Guillouzo A, Schmid J, Ludwig E, Sauter T.
Xenobiotica. 1998 Jan;28(1):1-13.

NAPROXEN
Cytochromes P450, 1A2, and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. [ PMID 8866821 ]
Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ.
Biochem Pharmacol 1996 Apr 26;51(8):1003-1008.

NATEGLINIDE
Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects. [ PMID 12968988 ]
Niemi M, Backman JT, Neuvonen M, Neuvonen PJ.
Clin Pharmacol Ther. 2003 Oct;74(4):380-7.

PHENYTOIN
Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. [ PMID 2025243 ]
Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO, Birkett DJ.
Biochem Biophys Res Commun. 1991;175(3):1112-1118.

Fluconazole-induced symptomatic phenytoin toxicity.[ PMID 8173131 ]
Cadle RM, Zenon GJ III, Rodriguez-Barradas MC, Hamill RJ.
Ann Pharmacother 1994;28(2) 191-194.

PIROXICAM
Involvement of multiple cytochrome P450 isoforms in naproxen O-demethylation. [ PMID 9248768 ]
Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, Korzekwa KR.
Eur J Clin Pharmacol. 1997; 52(4): 293-298.

Studies of flurbiprofen 4'-hydroxylation. Additional evidence suggesting the sole involvement of cytochrome P450 2C9. [ PMID 8937439 ]
Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, Korzekwa KR.
Biochem Pharmacol. 1996 Oct 25; 52(8): 1305-1309.

ROSIGLITAZONE
Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. [ PMID 12898007 ]
Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ.
Diabetologia. 2003 Oct;46(10):1319-23.

Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. [ PMID 15373932 ]
Park JY, Kim KA, Shin JG, Lee KY.
Br J Clin Pharmacol. 2004 Oct;58(4):397-402.

SUPROFEN
The substrate binding site of human liver cytochrome P450 2C9: an approach using designed tienilic acid derivatives and molecular modeling. [ PMID 7654690 ]
Mancy A, Broto P, Dijols S, Dansette PM, Mansuy D.
Biochemistry 1995 Aug 22;34(33):10365-10375.

TAMOXIFEN
Delineation of human cytochromes P450 involved in the metabolism of tamoxifen.
Daniels, L, Blankson, EA, Henderson, CJ, Harris, AH, Wolf, CR, Lennard, MS, and Tucker, GT.
Br J Clin Pharmacol 33:153P, 1992.

TORSEMIDE
Human hepatic Cytochrome P450 catalyses the rate-limiting pathway of torsemide metabolism. [ PMID 7891318 ]
Miners JO, Rees DLP, Valente L, Veronese ME, Birkett DJ.
J Pharmacol Exp Ther 1995;272(3):1076-1081.

TOLBUTAMIDE
Putative active site template model for cytochrome P4502C9 (Tolbutamide hydroxylase). [ PMID 8742240 ]
Jones BC, Hawksworth G, Horne VA, Newlands A, Morsman J, Tute MS, Smith DA.
Drug Metabolism and Disposition 1996;24(2):260-266.

NOT VALSARTAN
Pharmacokinetics of valsartan in patients with liver disease. [ PMID 9333102 ]
Brookman LJ, Rolan PE, Benjamin IS, Palmer KR, Wyld PJ, Lloyd P, Flesch G, Waldmeier F, Sioufi A, Mullins F.
Clinical Pharmacology and Therapeutics, 62 (3) 272-278 1997.

S-WARFARIN
Possible interaction between warfarin and fluconazole. [ PMID 8247921 ]
Gericke KR.
Pharmacotherapy 1993;13(5):508-509.

Possible potentiation of warfarin by fluconazole. [ PMID 2089826 ]
Seaton TL, Celum C.L., Black DJ.
Drug Intelligence Clin Pharmacol 1990;24:1177-1178.

Interactions of warfarin with drugs and food. [ PMID 7944078 ]
Wells PS, Holbrook AM, Crowther NR, Hirsh J.
Ann Intern Med 1994;121:676-683.

Inhibition of the human cytochrome P450- dependent metabolism of warfarin by fluconazole: in vitro studies. [ PMID 8801056 ]
Kunze KL, Wienkers LC, Thummel KE, Trager WF.
Drug Metab Dispos 1996;24(4):414-421.

A metabolically based drug interaction between fluconazole and warfarin: in vivo studies. [ PMID 8801057 ]
Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, Evans JS, Bauwens JE, Trager WF.
Drug Metab Dispos 1996;24(4):422-428.
 

 2C9 INHIBITORS: 

AMIODARONE
Mechanism of warfarin potentiation by amiodarone: dose--and concentration-dependent inhibition of warfarin elimination. [ PMID 4007030 ]
Almog S, Shafran N, Halkin H, Weiss P, Farfel Z, Martinowitz U, Bank H.
Eur J Clin Pharmacol 1985;28:257-261.

Steady-state interaction between amiodarone and phenytoin in normal subjects. [ PMID 2337037 ]
Nolan PE, Erstad BL, Hoyer GL, Bliss M, Gear K, Marcus FI.
Am J Cardiol 1990;65:1252-1257.

FLUCONAZOLE
Effect of fluconazole on the disposition of phenytoin. [ PMID 2015731 ]
Blum RA, Wilton JH, Hilligoss DM, Gardner MJ, Henry EU, Harrison NJ, Schentag JJ.
Clin Pharmacol Ther 1991;49:420-425.

Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies. [ PMID 8801056 ]
Kunze KL, Wienkers LC, Thummel KE, Trager WF.
Drug Metab Dispos. 1996 Apr;24(4):414-21.

Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. [ PMID 16413247 ]
Greenblatt DJ, von Moltke LL, Perloff ES, Luo Y, Harmatz JS, Zinny MA.
Clin Pharmacol Ther. 2006 Jan;79(1):125-33.

Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. [ PMID 9551703 ]
Kaukonen KM, Olkkola KT, Neuvonen PJ.
Eur J Clin Pharmacol. 1998 Feb;53(6):445-9.

FLUVASTATIN
In vivo inhibition profile of cytochrome P450tb (CYP2C9) by (±)-fluvastatin. [ PMID 7586933 ]
Transon C, Leemann T, Vogt N, Dayer P.
Clin Pharmacol Ther 1995;58(4):412-417.

FLUVOXAMINE
Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. [ PMID 10192756 ]
Hemeryck A, De Vriendt C, Belpaire FM.
Eur J Clin Pharmacol 1999 Feb;54(12):947-51.

ISONIAZID
Clinical importance of the interaction of phenytoin and isoniazid: a report of the Boston Collaborative Drug Surveillance Program. [ PMID 421578 ]
Miller RR, Porter J, Greenblatt DJ.
Chest 1979;75(3):356-358.

LOVASTATIN
Warfarin Interaction. [ PMID 2241455 ]
Ahmad S.
Arch Int Med 1990;150:2407-2408.

PHENYLBUTAZONE
Stereochemical aspects of warfarin drug interactions: Use of a combined pharmacokinetic- pharmacodynamic model. [ PMID 7924124 ]
Chan E, McLachlan A, O'Reilly, Rowland M.
Clin Pharmacol Ther 1994;56(3):286-294.

PROBENICID
Naproxen-probenecid interaction. [ PMID 710028 ]
Runkel R, Mroszczak E, Chaplin M, Sevelius H, Segre E.
Clin Pharmacol Ther 1978 Dec;24(6):706-713.

SERTRALINE
Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. [ PMID 9384467 ]
Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, Shader RI.
Br J Clin Pharmacol. 1997 Nov;44(5):495-8.

Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes. [ PMID 10510155 ]
Xu ZH, Wang W, Zhao XJ, Huang SL, Zhu B, He N, Shu Y, Liu ZQ, Zhou HH.
Br J Clin Pharmacol. 1999 Sep;48(3):416-23.

SULFAMETHOXAZOLE
Formation and disposition of sulfamethoxazole hydroxylamine (SMX-MA).
Spielberg SP, Nuss CE, Cribb AE.
Clin Pharmacol Ther 1995;57(2):221 Abst.

SULFAPHENAZOLE
In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides, and quinolines. [ PMID 3203057 ]
Back DJ, Tjia JF, Karbwang J, Colbert J.
Br J Clin Pharmacol 1988;26:23-29.

TENIPOSIDE
Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. [ PMID 2299601 ]
Relling MV, Aoyama T, Gonzalez FJ, Meyer UA.
J Pharmacol Exp Ther 1990 Jan;252(1):442-7.

TICLOPIDINE
Ticlopdine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. [ PMID 9390115 ]
Donahue SR, Flockhart DA, Abernethy DR, Ko JW.
Br Clin Pharmacol Ther 1997 Nov;62(5):572-7.

TRIMETHOPRIM

VORICONAZOLE
Effect of voriconazole on the pharmacokinetics of diclofenac. [ PMID 18034666 ]
Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A, Valtonen M, Laine K.
Fundam Clin Pharmacol. 2007 Dec;21(6):651-6.

Drug-drug interaction of antifungal drugs. [ PMID 16205037 ]
Niwa T, Shiraga T, Takagi A.
Yakugaku Zasshi. 2005 Oct;125(10):795-805.

ZARFIRLUKAST
(Accolate®) Prescriber's Letter 1996;3(10) 55. (October)


 2C9 INDUCERS: 

RIFAMPIN

SECOBARBITAL
Stereochemical aspects of warfarin drug interactions: use of a combined pharmacokinetic-pharmacodynamic model. [ PMID 7924124 ]
Chan E, McLachlan A, O'Reilly R, Rowland M.
Clin Pharmacol Ther 1994 Sep;56(3):286-294.