SCHOOL OF MEDICINE

Department of Medicine

Clinical Pharmacology

2C19 REFERENCES

 2C19 SUBSTRATES: 

CYP2C19 ITSELF
Isolation and Characterization of Human Liver Cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4'-hydroxylation. [ PMID 8215410 ]
Wrighton SA, Stevens JC, Becker GW and Vandenbranden M.
Pubmed Biochem Biophys 1993 Oct;306(1):240-245.

AMITRIPTYLINE
Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. [ PMID 9549641 ]
Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Schmider J, Harmatz JS, Shader RI.
Clin Pharmacol. 1998 Feb; 38(2): 112-121.

Metabolism of the tricyclic antidepressant amitriptyline by cDNA-expressed human cytochrome P450 enzymes. [ PMID 9399333 ]
Olesen OV, Linnet K.
Pharmacology. 1997 Nov; 55(5): 235-243.

Cytochromes P450 mediating the N-demethylation of amitriptyline. [ PMID 9131945 ]
Ghahramani P, Ellis SW, Lennard MS, Ramsay LE, Tucker GT.
Br J Clin Pharmacol. 1997 Feb; 43(2): 137-144.

CARISOPRODOL

CHLORAMPHENICOL
Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes. [ PMID 14576103 ]
Park JY, Kim KA, Kim SL.
Antimicrob Agents Chemother. 2003 Nov;47(11):3464-9.

CITALOPRAM
Personal communication with Dr. Terence Ketter about citalopram on March 29, 1995.
Ketter, TA.
Flockhart, DA 1995.

CLOMIPRAMINE
Pharmacogenetics of antidepressants: clinical aspects. [ PMID 9265947 ]
Bertilsson L, Dahl ML, Tybring G.
Acta Psychiatr Scand Suppl 1997;391:14-21.

CLOPIDOGREL
The Effect of CYP2C19 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Clopidogrel: A Possible Mechanism for Clopidogrel Resistance. [ PMID 18323861 ]
Kim K, Park P, Hong S, Park JY.
Clin Pharmacol Ther. 2008 Aug;84(2):236-42.

Genetic determinants of response to clopidogrel and cardiovascular events. [ PMID 19106083 ]
Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.
N Engl J Med. 2009 Jan 22;360(4):363-75.

CYCLOPHOSPHAMIDE
Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation. [ PMID 9241661 ]
Chang TKH, Yu L, Goldstein JA, Waxman DJ.
Pharmacogenetics 1997;7:211-221.

DIAZEPAM
Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. [ PMID 8148870 ]
Yasumori T, Nagata K, Yang SK, Chen L-S, Murayama N, Yamazoe Y, Kato R.
Pharmacogenetics 1993;3:291-301.

ESCITALOPRAM

HEXOBARBITAL
Stereoselective disposition of hexobarbital and its metabolites: relationship to the S-mephenytoin polymorphism in Caucasian and Chinese subjects. [ PMID 8004130 ]
Adedoyin A, Prakash C, O'Shea D, Blair IA, Wilkinson GR.
Pharmacogenetics. 1994 Feb; 4(1): 27-38.

Polymorphism in stereoselective hydroxylations of mephenytoin and hexobarbital by Japanese liver samples in relation to cytochrome P-450 human-2 (IIC9). [ PMID 1441599 ]
Kato R, Yamazoe Y, Yasumori T.
Xenobiotica. 1992 Sep; 22(9-10): 1083-1092. Review.

Polymorphism in hydroxylation of mephenytoin and hexobarbital stereoisomers in relation to hepatic P-450 human-2. [ PMID 2311333 ]
Yasumori T, Murayama N, Yamazoe Y, Kato R.
Clin Pharmacol Ther. 1990 Mar; 47(3): 313-322.

Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. [ PMID 3385644 ]
Knodell RG, Dubey RK, Wilkinson GR, Guengerich FP.
J Pharmacol Exp Ther. 1988 Jun; 245(3): 845-849.

IMIPRAMINE N-deME
Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. [ PMID 9190854 ]
Koyama E, Chiba K, Tani M, Ishizaki T.
J Pharmacol Exp Ther. 1997 Jun; 281(3): 1199-1210.

Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. [ PMID 8521680 ]
Bertilsson L.
Clin Pharmacokinet. 1995 Sep; 29(3): 192-209. Review.

INDOMETHACIN
Human cytochrome P4502C metabolism.
Weaver RJ, Webster D, Melvin WT, Dickins M and Burke MD.
Br J Clin Pharmacol 1993 April;36(2):167P.

LANSOPRAZOLE
Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4'-hydroxylation phenotype status. [ PMID 9164419 ]
Sohn DR, Kwon JT, Kim HK, Ishizaki T.
Clin Pharmacol Ther 1997 May;61(5):574-582.

S-MEPHENYTOIN
Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. [ PMID 6499356 ]
Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR, Branch RA.
Clin Pharmacol Ther, 1984 Dec; 36(6):773-780.

R-MEPHOBARBITAL
Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. [ PMID 4042524 ]
Kupfer A, Branch RA.
Clin Pharmacol Ther, 1985 Oct; 38(4):414-418.

MOCLOBEMIDE
Moclobemide: a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2: A panel study. [ PMID 7781267 ]
Gram LF, Guentert TW, Grange S, Vistisen K, Brøsen K.
Clin Pharmacol Ther 1995;57(6):670-677.

NELFINAVIR
Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. [ PMID 9660842 ]
Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shetty BV, Lee CA.
Drug Metab Dispos 1998 Jul;26(7):609-16.

NILUTAMIDE
Nilutamide inhibits mephenytoin 4-hydroxylation in untreated male rats and in human liver microsomes. [ PMID 1785203 ]
Horsmans Y, Lannes D, Larrey D, Tinel M, Letteron P, Loeper J, Pessayre D.
Xenobiotica 1991 Dec;21(12):1559-1570.

OMEPRAZOLE
Effect of omeprazole on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. [ PMID 2104790 ]
Andersson T, Cederberg C, Edvardsson G, Heggelund A, Lundborg P.
Clin Pharmacol Ther 1990;47(1):79-85.

OXCARBAZEPINE
Spotlight on oxcarbazepine in epilepsy. [ PMID 14731060 ]
Bang LM, Goa KL.
CNS Drugs. 2004;18(1):57-61.

PANTOPRAZOLE
Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4'-hydroxylation phenotype and genotype. [ PMID 9433390 ]
Tanaka M, Ohkubo T, Otani K, Suzuki A, Kaneko S, Sugawara K, Ryokawa Y, Hakusui H, Yamamori S, Ishizaki T.
Clin Pharmacol Ther 1997 Dec;62(6):619-628.

PHENYTOIN
Role of S-mephenytoin hydroxylase in the metabolism of phenytoin.
Bajpai M, Roskos LK, Shen DD, Trager WF, Levy RH.
Pharm Res 1994, 11(Suppl):S348.

PHENOBARBITONE
CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics.
Mamiya K, Hadama A, Yukawa E, Ieiri I, Otsubo K, Ninomiya H, Tashiro N, Higuchi S.
Eur J Clin Pharmacol 2000, 55:821-825.

PRIMIDONE

PROGESTERONE
Progesterone and testosterone hydroxylation by CYP 2C19, 2C9 and 3A4 in human liver microsomes. [ PMID 9328296 ]
Yamazaki H, Shimada T.
Arch Biochem Biophys 1997;346(1):161-169.

PROGUANIL
Metabolic Disposition of proguanil in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population. [ PMID 7619672 ]
Setiabudy R, Kusaka M, Chiba K, Darmansjah I, Ishizaki T.
Br J Clin Pharmacol 1995;39(3):297-303.

PROGUANIL
Metabolic Disposition of proguanil in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population. [ PMID 7619672 ]
Setiabudy R, Kusaka M, Chiba K, Darmansjah I, Ishizaki T.
Br J Clin Pharmacol 1995;39(3):297-303.

In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as S-mephenytoin hydroxylase. [ PMID 8054246 ]
Birkett DJ, Rees D, Andersson T, Gonzalex FJ, Miners JO, Veronese ME.
Br J Clin Pharmacol 1994;37:413-420.

The activation of the biguanide anti-malarial proguanil co-segregates with the mephenytoin oxidation polymorphism - a panel study. [ PMID 1867963 ]
Ward SA, Helsby NA, Skjelbo E, Brøsen K, Gram LF, Breckenridge AM.
Br J Clin Pharmacol 1991;31:689-692.

Relation between chloroguanide bioavtivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans. [ PMID 1587064 ]
Funck-Brentano C, Bosco O, Jacqz-Aigrain E, KeunjiN a, Jaillon P.
Clin Pharmacol Ther 1992;51(5):507-512.

PROPRANOLOL
Not in vitro. Propranolol oxidation by human liver microsomes-- use of cumene hydroperoxide to probe isoenzyme specificity and regio- and stereoselectivity. [ PMID 2271375 ]
Otton SV, Gillam EM, Lennard MS, Tucker GT, Woods HF.
Br J Clin Pharmacol 1990 Nov;30(5):751-760.

RABEPRAZOLE
Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19. [ PMID 16413249 ]
Shimatani T, Inoue M, Kuroiwa T, Xu J, Mieno H, Nakamura M, Tazuma S.
Clin Pharmacol Ther. 2006 Jan;79(1):144-52.

R-WARFARIN
Correlation of human cytochrome P450 2C substrate specificities with primary structure: warfarin as a probe. [ PMID 8429826 ]
Kaminsky LS, de Morais SM, Faletto MB, Dunbar DA, Goldstein JA.
Mol Pharmacol 1993;43:234-239.

TENIPOSIDE

 2C19 INHIBITORS: 

CIMETIDINE
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.

CHLORAMPHENICOL
Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes. [ PMID 14576103 ]
Park JY, Kim KA, Kim SL.
Antimicrob Agents Chemother. 2003 Nov;47(11):3464-9.

FELBAMATE

FLUOXETINE
Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. [ PMID 16679385 ]
McGinnity DF, Berry AJ, Kenny JR, Grime K, Riley RJ.
Drug Metab Dispos. 2006 Aug;34(8):1291-300.

Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers. [ PMID 11270912 ]
Harvey AT, Preskorn SH.
J Clin Psychopharmacol. 2001 Apr;21(2):161-6.

Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. [ PMID 8880055 ]
Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K.
Eur J Clin Pharmacol. 1996;51(1):73-8.

The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes. [ PMID 8703653 ]
Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y.
Br J Clin Pharmacol. 1995 Nov;40(5):481-5.

FLUVOXAMINE
Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. [ PMID 17596106 ]
von Richter O, Lahu G, Huennemeyer A, Herzog R, Zech K, Hermann R.
Clin Pharmacokinet. 2007;46(7):613-22.

Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes. [ PMID 15025747 ]
Yasui-Furukori N, Takahata T, Nakagami T, Yoshiya G, Inoue Y, Kaneko S, Tateishi T.
Br J Clin Pharmacol. 2004 Apr;57(4):487-94.

Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles. [ PMID 12698310 ]
Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T.
Eur J Clin Pharmacol. 2003 Apr;58(12):829-33.

INDOMETHACIN
Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. [ PMID 9492390 ]
Nakajima M, Inoue T, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y.
Drug Metab Dispos. 1998 Mar;26(3):261-6.

KETOCONAZOLE
Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible. [ PMID 14709627 ]
Stresser DM, Broudy MI, Ho T, Cargill CE, Blanchard AP, Sharma R, Dandeneau AA, Goodwin JJ, Turner SD, Erve JC, Patten CJ, Dehal SS, Crespi CL.
Drug Metab Dispos. 2004 Jan;32(1):105-12.

In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: a comparison with SKF-525A and ketoconazole. [ PMID 15618748 ]
Emoto C, Murase S, Sawada Y, Jones BC, Iwasaki K.
Drug Metab Pharmacokinet. 2003;18(5):287-95.

LANSOPRAZOLE
Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. [ PMID 9224780 ]
Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA.
Eur J Clin Pharmacol 1985;28:257-261.

Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. [ PMID 15258107 ]
Li XQ, Andersson TB, Ahlström M, Weidolf L.
Drug Metab Dispos. 2004 Aug;32(8):821-7.

Stereoselective inhibition of cytochrome P450 forms by lansoprazole and omeprazole in vitro. [ PMID 15788366 ]
Liu KH, Kim MJ, Shon JH, Moon YS, Seol SY, Kang W, Cha IJ, Shin JG.
Xenobiotica. 2005 Jan;35(1):27-38.

MODAFINIL
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. [ PMID 10820139 ]
Robertson P, DeCory HH, Madan A, Parkinson A.
Drug Metab Dispos. 2000 Jun;28(6):664-71.

OMEPRAZOLE
Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. [ PMID 9224780 ]
Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA.
Eur J Clin Pharmacol 1985;28:257-261.

OXCARBAZEPINE
Spotlight on oxcarbazepine in epilepsy. [ PMID 14731060 ]
Bang LM, Goa KL.
CNS Drugs. 2004;18(1):57-61.

Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19. [ PMID 12458024 ]
Lakehal F, Wurden CJ, Kalhorn TF, Levy RH.
Epilepsy Res. 2002 Dec;52(2):79-83.

PANTOPRAZOLE
Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4'-hydroxylation phenotype and genotype. [ PMID 9433390 ]
Tanaka M, Ohkubo T, Otani K, Suzuki A, Kaneko S, Sugawara K, Ryokawa Y, Hakusui H, Yamamori S, Ishizaki T.
Clin Pharmacol Ther 1997 Dec;62(6):619-628.

PROBENICID

RABEPRAZOLE
Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19. [ PMID 16413249 ]
Shimatani T, Inoue M, Kuroiwa T, Xu J, Mieno H, Nakamura M, Tazuma S.
Clin Pharmacol Ther. 2006 Jan;79(1):144-52.

Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status. [ PMID 16487224 ]
Uno T, Shimizu M, Yasui-Furukori N, Sugawara K, Tateishi T.
Br J Clin Pharmacol. 2006 Mar;61(3):309-14.

TICLOPIDINE
Interaction magnitude, pharmacokinetics and pharmacodynamics of ticlopidine in relation to CYP2C19 genotypic status. [ PMID 16272957 ]
Ieiri I, Kimura M, Irie S, Urae A, Otsubo K, Ishizaki T.
Pharmacogenet Genomics. 2005 Dec;15(12):851-9.

Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism. [ PMID 10233213 ]
Tateishi T, Kumai T, Watanabe M, Nakura H, Tanaka M, Kobayashi S.
Br J Clin Pharmacol. 1999 Apr;47(4):454-7.

Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. [ PMID 11580286 ]
Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D.
Biochemistry. 2001 Oct 9;40(40):12112-22.

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

TOPIRAMATE
Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. [ PMID 12102670 ]
Sachdeo RC, Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kunze KL, Mather GG, Roskos LK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Bialer M.
Epilepsia. 2002 Jul;43(7):691-6.


 2C19 INDUCERS: 

CARBAMAZEPINE

NORETHINDRONE

NOT PENTOBARBITAL
Influence of enzyme induction and inhibition on the oxidation of nifedipine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design. [ PMID 2724144 ]
Schellens JHM, van der Wart JHF, Brugman M, Breimer DD.
J Pharmac Exp Ther 1989;249(2):638-645.

PREDNISONE
Influence of corticosteroid on hexobarbital and tolbutamide disposition. [ PMID 679598 ]
Breimer DD, Zilly W, Richter E.
Clin Pharmacol Ther 1978 Aug;24(2):208-212.

RIFAMPICIN
Induction of polymorphic 4'-hydroxylation of S-mephenytoin by rifampicin. [ PMID 2223426 ]
Zhou HH, Anthony LB, Wood AJJ, Wilkinson GR.
Br J Clin Pharmacol 1990;30:471-475.