Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone

Summary

The purpose of this study is to determine to what extent CYP2B6, CYP3A4, and MDR1 polymorphisms affect the metabolism of methadone.

Timeline

Start

2007-07

Primary completion

2011-01

Completion

2011-01

Publications

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• Background Wong KH, Lee SS, Lim WL, Low HK. Adherence to methadone is associated with a lower level of HIV-related risk behaviors in drug users. J Subst Abuse Treat. 2003 Apr;24(3):233-9. doi: 10.1016/s0740-5472(03)00029-1.
• Background Bruera E, Kim HN. Cancer pain. JAMA. 2003 Nov 12;290(18):2476-9. doi: 10.1001/jama.290.18.2476. No abstract available.
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• Background Shinderman M, Maxwell S, Brawand-Amey M, Golay KP, Baumann P, Eap CB. Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses. Drug Alcohol Depend. 2003 Mar 1;69(2):205-11. doi: 10.1016/s0376-8716(02)00320-4.
• Background Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003.
• Background Foster DJ, Somogyi AA, Dyer KR, White JM, Bochner F. Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients. Br J Clin Pharmacol. 2000 Nov;50(5):427-40. doi: 10.1046/j.1365-2125.2000.00272.x.
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• Background Oda Y, Kharasch ED. Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation. J Pharmacol Exp Ther. 2001 Sep;298(3):1021-32.
• Background Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos. 2003 Jun;31(6):742-7. doi: 10.1124/dmd.31.6.742.
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• Background Hesse LM, Sakai Y, Vishnuvardhan D, Li AP, von Moltke LL, Greenblatt DJ. Effect of bupropion on CYP2B6 and CYP3A4 catalytic activity, immunoreactive protein and mRNA levels in primary human hepatocytes: comparison with rifampicin. J Pharm Pharmacol. 2003 Sep;55(9):1229-39. doi: 10.1211/0022357021657.
• Background Martin H, Sarsat JP, de Waziers I, Housset C, Balladur P, Beaune P, Albaladejo V, Lerche-Langrand C. Induction of cytochrome P450 2B6 and 3A4 expression by phenobarbital and cyclophosphamide in cultured human liver slices. Pharm Res. 2003 Apr;20(4):557-68. doi: 10.1023/a:1023234429596.
• Background Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004 Sep 15;199(3):193-209. doi: 10.1016/j.taap.2004.01.010.
• Background Pascussi JM, Gerbal-Chaloin S, Drocourt L, Maurel P, Vilarem MJ. The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta. 2003 Feb 17;1619(3):243-53. doi: 10.1016/s0304-4165(02)00483-x.
• Background Crettol S, Deglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hammig R, Monnat M, Huttemann H, Baumann P, Eap CB. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005 Dec;78(6):593-604. doi: 10.1016/j.clpt.2005.08.011.
• Background Lotsch J, Skarke C, Wieting J, Oertel BG, Schmidt H, Brockmoller J, Geisslinger G. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther. 2006 Jan;79(1):72-89. doi: 10.1016/j.clpt.2005.09.010.
• Background Miksys S, Lerman C, Shields PG, Mash DC, Tyndale RF. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology. 2003 Jul;45(1):122-32. doi: 10.1016/s0028-3908(03)00136-9.
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• Background Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther. 2000 Feb;38(2):69-74. doi: 10.5414/cpp38069.
• Background Lamba J, Strom S, Venkataramanan R, Thummel KE, Lin YS, Liu W, Cheng C, Lamba V, Watkins PB, Schuetz E. MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype. Clin Pharmacol Ther. 2006 Apr;79(4):325-38. doi: 10.1016/j.clpt.2005.11.013. Epub 2006 Feb 20.
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• Background Kharasch ED, Hoffer C, Whittington D. The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol. 2004 May;57(5):600-10. doi: 10.1111/j.1365-2125.2003.02053.x.
• Background Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL. Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice. Psychopharmacology (Berl). 2004 Apr;173(1-2):132-8. doi: 10.1007/s00213-003-1718-1. Epub 2004 Jan 8.
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