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

The recruitment status of this study is unknown because the information has not been verified recently.

Verified October 2010 by University of Washington.
Recruitment status was Recruiting

Sponsor:

Information provided by:

University of Washington

ClinicalTrials.gov Identifier:

NCT00504413

First received: July 18, 2007

Last updated: October 11, 2010

Last verified: October 2010

History of Changes

Purpose

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

Condition	Intervention	Phase
Substance-Related Disorders	Drug: midazolam(drug), digoxin (drug) Drug: Bupropion (drug) Drug: Methadone (drug)	Phase 1

Study Type:	Interventional
Study Design:	Endpoint Classification: Pharmacokinetics Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Basic Science
Official Title:	Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone in Human Subjects

Resource links provided by NLM:

Drug Information available for: Methadone Methadone hydrochloride Digoxin Bupropion hydrochloride Bupropion Midazolam hydrochloride

U.S. FDA Resources

Further study details as provided by University of Washington:

Primary Outcome Measures:

Explore if there is a correlation between the areas of the concentration curves of probe substrates for CYP3A4 and/or CYP2B6 and Pgp and the area of the concentration curve of methadone. [ Time Frame: two years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

LC-MS assays will be developed to analyze the plasma content of the probe substrates, methadone and their metabolites. Specifically, midazolam, 1-OH midazolam, bupropion, t-butyl-hydroxy bupropion, digoxin, methadone, and EDDP (a methadone metabolite). [ Time Frame: two years ] [ Designated as safety issue: No ]
Isolate and bank the DNA of the subjects for future genotyping of variant alleles that will be identified in this study to be important in methadone pharmacokinetics. [ Time Frame: two years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	20
Study Start Date:	July 2007
Estimated Study Completion Date:	January 2011
Estimated Primary Completion Date:	January 2011 (Final data collection date for primary outcome measure)

Intervention Details:

Midazolam (2mg po) and digoxin (0.5mg po) will be administered one time, an hour apart. Blood concentration will be collected at various points in an 8 hour period.

Bupropion (150mg po) will be administered one time on a separate visit. Blood concentrations will be collected at various points in a 72 hour period.

Other Name: Wellbutrin

Methadone (10mg po) will be administered at a separate visit 2 weeks after the bupropion visit. The dose is given once. Blood concentrations will be measured at various points in a 72 hour period. Pupil constriction will be measured and urine will be collected during this period as well.

Detailed Description:

Methadone maintenance treatment (MMT) has been used to rehabilitate the opiate addict resulting in a higher quality of life for the patient as well as improving social and psychological functioning while reducing the overall cost to society. The maintenance dose of methadone is highly variable between patients, and drug-drug interactions have been observed between methadone and various medications used to treat a variety of diseases. Identification and understanding of the enzymes responsible for the metabolism of methadone could potentially lead to improved strategy in individualizing methadone dosing and reduce the risk of adverse drug interactions.

Several cytochrome P450 enzymes (CYPs) have been identified and hypothesized to be involved in methadone metabolism in vitro, particularly CYP2B6 and CYP3A4. However, the quantitative contribution of CYP2B6 and CYP3A4 in the elimination clearance of methadone in vivo remains undefined. In addition, methadone is a substrate of the efflux transporter, P-glycoprotein (Pgp) at the intestinal mucosa. We are proposing a pilot study in healthy human subjects to investigate the following hypotheses:

Pgp limits the gastrointestinal absorption
Inter-subject variations in CYP2B6 and CYP3A4 activities explain the variation in methadone clearance in vivo

This will be accomplished by correlating the pharmacokinetics of methadone and the phenotype probes for Pgp (digoxin), CYP2B6 (bupropion) and CYP3A4 (midazolam). We plan to use these data to design a human subject study to assess the utility of MDR1 and CYP genotyping in predicting the methadone maintenance dose in a cohort of MMT patients.

Eligibility

Ages Eligible for Study:	18 Years to 40 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Healthy
Within 25% of ideal body weight

Exclusion Criteria:

Pregnant
A prisoner
Enemy, non-combatant
Smoker
Have a history of liver disease
Have a history of heart disease
Have a history of drug abuse
Currently on prescription medication

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00504413

Contacts

Contact: Jean C Dinh, PharmD	206.616.2775	jeandinh@u.washington.edu
Contact: Rheem A Totah, PhD	206.543.9481	rtotah@u.washington.edu

Locations

United States, Washington
University of Washington General Clinical Research Center	Recruiting
Seattle, Washington, United States, 98105
Principal Investigator: Rheem A Totah, PhD
Principal Investigator: Danny Shen, PhD
Sub-Investigator: Gregory Terman, MD
Sub-Investigator: Kristin K Patton, MD
Sub-Investigator: Jean C Dinh, BS

Sponsors and Collaborators

University of Washington

Investigators

Principal Investigator:

Rheem A Totah, PhD

University of Washington, Medicinal Chemistry Department

More Information

Publications:

Beckett AH, Taylor JF, Casy AF, Hassan MM. The biotransformation of methadone in man: synthesis and identification of a major metabolite. J Pharm Pharmacol. 1968 Oct;20(10):754-62. No abstract available.

Kreek MJ, Vocci FJ. History and current status of opioid maintenance treatments: blending conference session. J Subst Abuse Treat. 2002 Sep;23(2):93-105. Review.

Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2003;(2):CD002209. Review.

Brettle RP. HIV and harm reduction for injection drug users. AIDS. 1991 Feb;5(2):125-36. Review. No abstract available.

Ward J, Mattrick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, Amsterdam. 1998

Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust. 1999 Feb 1;170(3):104-9.

Sorensen JL, Copeland AL. Drug abuse treatment as an HIV prevention strategy: a review. Drug Alcohol Depend. 2000 Apr 1;59(1):17-31. Review.

Stenbacka M, Leifman A, Romelsjo A. The impact of methadone treatment on registered convictions and arrests in HIV-positive and HIV-negative men and women with one or more treatment periods. Drug Alcohol Rev. 2003 Mar;22(1):27-34.

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.

Bruera E, Kim HN. Cancer pain. JAMA. 2003 Nov 12;290(18):2476-9. Review. No abstract available.

Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. 1986 Jun;25(3):297-312.

Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain. 1997 Mar;70(1):99-101.

Mercandante, S. Methadone in cancer pain. Eur J Pain 1:77, 1997.

Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol Oncol Clin North Am. 2002 Jun;16(3):543-55. Review.

Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56(2):PL45-50.

Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap CB. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol. 2002 Apr;22(2):211-5.

Inturrisi CE, Verebely K. Disposition of methadone in man after a single oral dose. Clin Pharmacol Ther. 1972 Nov-Dec;13(6):923-30. No abstract available.

Hanna J, Foster DJ, Salter A, Somogyi AA, White JM, Bochner F. Within- and between- subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects. Br J Clin Pharmacol. 2005 Oct;60(4):404-13.

Peles E, Schreiber S, Gordon J, Adelson M. Significantly higher methadone dose for methadone maintenance treatment (MMT) patients with chronic pain. Pain. 2005 Feb;113(3):340-6.

Charlier C, Dessalles MC, Plomteux G. Methadone maintenance treatment: is it possible to adapt the daily doses to the metabolic activity of the patient? Ther Drug Monit. 2001 Feb;23(1):1-3.

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.

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. Review.

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.

Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F. Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology. 1997 Feb 14;117(1):13-23.

Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet. 2003;42(9):819-50. Review.

Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality. 2004 Jan;16(1):36-44.

Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther. 2004 Sep;76(3):250-69.

Moody DE, Walsh SL, Rollins DE, Neff JA, Huang W. Ketoconazole, a cytochrome P450 3A4 inhibitor, markedly increases concentrations of levo-acetyl-alpha-methadol in opioid-naive individuals. Clin Pharmacol Ther. 2004 Aug;76(2):154-66.

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.

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.

Boulton DW, Arnaud P, DeVane CL. Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther. 2001 Jul;70(1):48-57.

Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL. Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58.

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.

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.

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. Review.

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. Review.

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.

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.

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.

Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica. 1998 Dec;28(12):1203-53. Review. No abstract available.

de Boer AG, van der Sandt IC, Gaillard PJ. The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol. 2003;43:629-56. Epub 2002 Jan 10. Review.

Fricker G, Miller DS. Relevance of multidrug resistance proteins for intestinal drug absorption in vitro and in vivo. Pharmacol Toxicol. 2002 Jan;90(1):5-13. Review.

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. Review.

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. Epub 2006 Feb 20.

Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet. 2003;42(1):59-98. Review.

Bouer R, Barthe L, Philibert C, Tournaire C, Woodley J, Houin G. The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac. Fundam Clin Pharmacol. 1999;13(4):494-500.

Callaghan R, Riordan JR. Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J Biol Chem. 1993 Jul 25;268(21):16059-64.

Stormer E, Perloff MD, von Moltke LL, Greenblatt DJ. Methadone inhibits rhodamine123 transport in Caco-2 cells. Drug Metab Dispos. 2001 Jul;29(7):954-6.

Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology. 2000 May;92(5):1392-9.

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.

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. Epub 2004 Jan 8.

Streetman DS, Bertino JS Jr, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics. 2000 Apr;10(3):187-216. Review.

Streetman DS, Bleakley JF, Kim JS, Nafziger AN, Leeder JS, Gaedigk A, Gotschall R, Kearns GL, Bertino JS Jr. Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail". Clin Pharmacol Ther. 2000 Oct;68(4):375-83.

Doherty JE, Flanigan WJ, Murphy ML, Bulloch RT, Dalrymple GL, Beard OW, Perkins WH. Tritiated digoxin. XIV. Enterohepatic circulation, absorption, and excretion studies in human volunteers. Circulation. 1970 Nov;42(5):867-73. No abstract available.

Klotz U, Antonin KH. Biliary excretion studies with digoxin in man. Int J Clin Pharmacol Biopharm. 1977 Jul;15(7):332-4.

Palovaara S, Pelkonen O, Uusitalo J, Lundgren S, Laine K. Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation. Clin Pharmacol Ther. 2003 Oct;74(4):326-33.

Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H, Pelkonen O. Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos. 2004 Jun;32(6):626-31.

Rosner B. Fundamentals of Biostatistics. Duxbury, 2006.

Whittington D, Sheffels P, Kharasch ED. Stereoselective determination of methadone and the primary metabolite EDDP in human plasma by automated on-line extraction and liquid chromatography mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Oct 5;809(2):313-21.

Jabor VA, Coelho EB, Dos Santos NA, Bonato PS, Lanchote VL. A highly sensitive LC-MS-MS assay for analysis of midazolam and its major metabolite in human plasma: applications to drug metabolism. J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Aug 5;822(1-2):27-32.

Tracqui A, Kintz P, Ludes B, Mangin P. High-performance liquid chromatography-ionspray mass spectrometry for the specific determination of digoxin and some related cardiac glycosides in human plasma. J Chromatogr B Biomed Sci Appl. 1997 Apr 25;692(1):101-9.

Hsyu PH, Singh A, Giargiari TD, Dunn JA, Ascher JA, Johnston JA. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J Clin Pharmacol. 1997 Aug;37(8):737-43.

Responsible Party:	Rheem Totah/Assistant Professor, Medicinal Chemistry, University of Washington
ClinicalTrials.gov Identifier:	NCT00504413 History of Changes
Other Study ID Numbers:	30931-A, 06-3659-A 01
Study First Received:	July 18, 2007
Last Updated:	October 11, 2010
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Washington:

Metabolic Networks and Pathways
Methadone
Polymorphism, genetic
Cytochrome P-450 Enzyme System

Additional relevant MeSH terms:

Substance-Related Disorders
Mental Disorders
Digoxin
Midazolam
Methadone
Bupropion
Cardiotonic Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Arrhythmia Agents
Protective Agents
Physiological Effects of Drugs

Adjuvants, Anesthesia
Central Nervous System Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Hypnotics and Sedatives
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Analgesics, Opioid
Analgesics

ClinicalTrials.gov processed this record on May 23, 2013

To Top