Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort.

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    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101131135 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-8100 (Electronic) Linking ISSN: 15362310 NLM ISO Abbreviation: OMICS Subsets: MEDLINE
    • Publication Information:
      Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., c2002-
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    • Abstract:
      Abstract Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram (p=0.021), and the Treatment Emergent Symptom Scale (TESS) total score (p=0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone (p=0.035), and showed a lower plasma R-methadone/methadone dose ratio (p=0.007) in urine opiate test negative patients, as well as a greater QTc change (p=0.008) and higher total scores of TESS (p=0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.
    • References:
      J Pharmacol Exp Ther. 2007 Apr;321(1):389-99. (PMID: 17259447)
      Am J Drug Alcohol Abuse. 2012 May;38(3):213-9. (PMID: 22352836)
      Pharmacogenomics J. 2009 Dec;9(6):380-94. (PMID: 19636337)
      Drug Metab Dispos. 2001 Mar;29(3):242-51. (PMID: 11181490)
      Am J Pharmacogenomics. 2003;3(5):303-15. (PMID: 14575519)
      Drug Alcohol Depend. 2000 Dec 22;61(1):47-54. (PMID: 11064183)
      PLoS One. 2011 May 12;6(5):e19527. (PMID: 21589866)
      Clin Pharmacol Ther. 2006 Dec;80(6):668-81. (PMID: 17178267)
      Pharmacol Ther. 2007 Dec;116(3):496-526. (PMID: 18001838)
      Biotechniques. 2002 Jun;Suppl:62-6, 68-9. (PMID: 12083400)
      Bioinformatics. 2005 Jan 15;21(2):263-5. (PMID: 15297300)
      Clin Biochem. 2005 Apr;38(4):335-50. (PMID: 15766735)
      J Palliat Med. 2010 Jan;13(1):33-8. (PMID: 19824814)
      J Pharmacol Exp Ther. 2002 Nov;303(2):688-94. (PMID: 12388652)
      Pharmacogenomics. 2011 Nov;12(11):1525-33. (PMID: 21902500)
      Lancet. 2007 Feb 3;369(9559):366; author reply 366-7. (PMID: 17276767)
      Drug Metab Dispos. 2003 Jun;31(6):742-7. (PMID: 12756206)
      Anesthesiology. 2008 Mar;108(3):363-74. (PMID: 18292673)
      Drug Alcohol Depend. 2009 Jan 1;99(1-3):327-32. (PMID: 18774239)
      J Clin Psychopharmacol. 2004 Aug;24(4):446-8. (PMID: 15232338)
      Clin Pharmacol Ther. 2005 Dec;78(6):593-604. (PMID: 16338275)
      Clin Pharmacol Ther. 2007 May;81(5):719-28. (PMID: 17329992)
      Arch Intern Med. 2010 Mar 22;170(6):529-36. (PMID: 20308640)
      Drug Metab Rev. 2003 May-Aug;35(2-3):99-106. (PMID: 12959412)
      J Pharmacol Exp Ther. 1998 Jan;284(1):356-61. (PMID: 9435198)
      Drug Alcohol Depend. 2012 Jan 1;120(1-3):74-80. (PMID: 21782351)
      Am J Med. 2008 Sep;121(9):e11, author reply e13. (PMID: 18724943)
      Br J Clin Pharmacol. 2001 Oct;52(4):349-55. (PMID: 11678778)
      J Clin Psychopharmacol. 2011 Aug;31(4):463-9. (PMID: 21694616)
      J Anal Toxicol. 2012 May;36(4):239-49. (PMID: 22511698)
      Mol Pharmacol. 1994 Oct;46(4):594-8. (PMID: 7969038)
      Pharmacogenomics. 2011 Oct;12(10):1397-406. (PMID: 21902501)
      Chirality. 2004 Jan;16(1):36-44. (PMID: 14628297)
      Ther Drug Monit. 1996 Jun;18(3):221-7. (PMID: 8738759)
      Cardiology. 2009;113(1):59-65. (PMID: 18984955)
      Eur J Clin Pharmacol. 2009 Mar;65(3):281-5. (PMID: 18982321)
      Biomed Chromatogr. 2010 Jul;24(7):782-8. (PMID: 19904716)
      J Pharmacol Exp Ther. 2003 Jul;306(1):287-300. (PMID: 12676886)
      Br J Clin Pharmacol. 2008 Apr;65(4):548-57. (PMID: 17922881)
      Pharmacogenomics. 2010 Apr;11(4):537-46. (PMID: 20350136)
      Basic Clin Pharmacol Toxicol. 2011 Jan;108(1):55-62. (PMID: 20825389)
      J Clin Psychopharmacol. 2009 Feb;29(1):77-81. (PMID: 19142113)
      Expert Opin Drug Saf. 2007 May;6(3):289-303. (PMID: 17480178)
      Clin Pharmacol Ther. 2006 Jul;80(1):33-40. (PMID: 16815315)
      Br J Clin Pharmacol. 2006 Aug;62(2):250-2. (PMID: 16842404)
      Int Immunopharmacol. 2004 Nov;4(12):1525-30. (PMID: 15351321)
      Arch Intern Med. 2006 Jun 26;166(12):1280-7. (PMID: 16801510)
    • Accession Number:
      EC (Aryl Hydrocarbon Hydroxylases)
      EC (CYP2C19 protein, human)
      EC (Cytochrome P-450 CYP2C19)
      UC6VBE7V1Z (Methadone)
    • Publication Date:
      Date Created: 20130911 Date Completed: 20140417 Latest Revision: 20211021
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