title: Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent.
abstract: Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20 mg oral dose of omeprazole on two occasions: with a single 600 mg efavirenz dose; and after a 17-day treatment with efavirenz (600 mg per day). DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by liquid chromatography/tandem mass spectrometry. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (P<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: V
authors: V
authors: Michaud
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: Y
authors: Y
authors: Kreutz
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: T
authors: T
authors: Skaar
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: E
authors: E
authors: Ogburn
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: N
authors: N
authors: Thong
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: D A
authors: DA
authors: Flockhart
authors: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors: Z
authors: Z
authors: Desta
mesh_terms: D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000008:administration & dosage*; D003521:Cyclopropanes; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage*; D011110:Polymorphism, Genetic
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D009853:Omeprazole
references: Antimicrob Agents Chemother. 2007 Oct;51(10):3617-26
references: 17646413
references: AIDS. 2004 Dec 3;18(18):2391-400
references: 15622315
references: Clin Pharmacol Ther. 2000 Dec;68(6):598-604
references: 11180019
references: Biochem Biophys Res Commun. 2004 Jul 9;319(4):1322-6
references: 15194512
references: Drug Metab Dispos. 2000 Aug;28(8):966-72
references: 10901708
references: Clin Pharmacokinet. 2002;41(12):913-58
references: 12222994
references: Br J Clin Pharmacol. 1998 Jan;45(1):27-9
references: 9489590
references: Clin Pharmacol Ther. 2012 Mar;91(3):475-82
references: 22318618
references: Ann Pharmacother. 2010 Oct;44(10):1572-8
references: 20841522
references: J Pharmacol Exp Ther. 2007 Jan;320(1):72-80
references: 17041008
references: Drug Metab Dispos. 2009 Sep;37(9):1793-6
references: 19487252
references: Clin Pharmacol Ther. 2006 Jan;79(1):103-13
references: 16413245
references: Clin Pharmacol Ther. 2010 Nov;88(5):676-84
references: 20881953
references: Antimicrob Agents Chemother. 2009 Jun;53(6):2346-53
references: 19223624
references: Circulation. 2010 Feb 2;121(4):512-8
references: 20083681
references: Drug Metab Dispos. 2004 Sep;32(9):1008-14
references: 15319343
references: Clin Pharmacol Ther. 2008 Nov;84(5):589-94
references: 18650803
references: Br J Clin Pharmacol. 2010 Mar;69(3):222-30
references: 20233192
references: J Clin Pharmacol. 2004 Jun;44(6):577-81
references: 15145964
references: Pharmacogenet Genomics. 2005 Jan;15(1):1-5
references: 15864119
references: Xenobiotica. 2011 Jun;41(6):437-44
references: 21319958
references: J Clin Pharmacol. 2003 Nov;43(11):1211-5
references: 14551175
references: Pharmacogenomics J. 2013 Dec;13(6):484-9
references: 23089673
references: Clin Pharmacol Ther. 2004 Mar;75(3):191-7
references: 15001970
references: Antimicrob Agents Chemother. 2009 Jul;53(7):2791-8
references: 19433561
references: Pharmacogenomics. 2007 Jun;8(6):547-58
references: 17559344
references: Br J Clin Pharmacol. 2008 May;65(5):767-74
references: 18294333
references: J Clin Pharmacol. 2001 Jan;41(1):85-91
references: 11225565
references: Eur J Clin Pharmacol. 2006 Aug;62(8):621-5
references: 16791583
references: Clin Pharmacol Ther. 2008 Feb;83(2):322-7
references: 17625515
references: Clin Pharmacol Ther. 2005 Jul;78(1):25-33
references: 16003289
references: Eur J Clin Pharmacol. 2008 Jun;64(6):583-7
references: 18214455
references: Eur J Clin Pharmacol. 2009 Mar;65(3):281-5
references: 18982321
references: Drug Metab Dispos. 1999 Nov;27(11):1319-33
references: 10534318
references: BMC Clin Pharmacol. 2007 Jul 11;7:6
references: 17623107
references: Clin Drug Investig. 2008;28(5):263-79
references: 18407713
references: J Clin Pharmacol. 2004 Jun;44(6):582-9
references: 15145965
references: Clin Pharmacol Ther. 2005 Jul;78(1):1-6
references: 16003286
references: Clin Pharmacol Ther. 2004 Apr;75(4):298-309
references: 15060508
references: Eur J Clin Pharmacol. 2007 Feb;63(2):143-9
references: 17203292
references: Clin Pharmacol Ther. 1998 Aug;64(2):160-7
references: 9728896
references: J Pharmacol Exp Ther. 2003 Jul;306(1):287-300
references: 12676886
references: Br J Clin Pharmacol. 1990 Sep;30(3):471-5
references: 2223426
references: Fundam Clin Pharmacol. 1999;13(6):671-5
references: 10626755
references: Clin Pharmacol Ther. 2002 Jul;72(1):1-9
references: 12151999