Methadone: A substrate and mechanism-based inhibitor of CYP19 (aromatase)

Drug Metabolism and Disposition

Volumn 38, Issue 8, 2010, Pages 1308-1313

  Lu, Wenjie Jessie ^a   Bies, Robert ^a   Kamden, Landry K ^a   Desta, Zeruesenay ^a   Flockhart, David A ^a  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 ETHYL 5 METHYL 3,3 DIPHENYLPYRROLINE; 2 ETHYLIDENE 1,5 DIMETHYL 3,3 DIPHENYLPYRROLIDINE; AROMATASE; AROMATASE INHIBITOR; ESTRADIOL; METHADONE; TESTOSTERONE; UNCLASSIFIED DRUG;

ARTICLE; DRUG MECHANISM; DRUG METABOLISM; DRUG STRUCTURE; FEMALE; HUMAN; POSTMENOPAUSE; PRIORITY JOURNAL; TESTOSTERONE METABOLISM;

ANALGESICS, OPIOID; ANDROGENS; AROMATASE; AROMATASE INHIBITORS; ESTRADIOL; ESTROGENS; HUMANS; KINETICS; METHADONE; MICROSOMES; PYRROLIDINES; RECOMBINANT PROTEINS; TESTOSTERONE;

EID: 77954945999     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.110.032474     Document Type: Article

References (36)

1. Bäckström T (1995) Symptoms related to the menopause and sex steroid treatments. Ciba Found Symp 191:171-180.
2. Deshmukh SV, Nanovskaya TN, and Ahmed MS (2003) Aromatase is the major enzyme metabolizing buprenorphine in human placenta. J Pharmacol Exp Ther 306:1099-1105.
3. Eap CB, Bourquin M, Martin J, Spagnoli J, Livoti S, Powell K, Baumann P, and Déglon J (2000) Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend 61:47-54.
4. Eap CB, Buclin T, and Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41:1153-1193. (Pubitemid 35398691)
5. Foster DJ, Somogyi AA, and Bochner F (1999) Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 47:403-412.
6. Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, and Dale O (2008) Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand 52:879-889.
7. Hallinan R, Byrne A, Agho K, McMahon CG, Tynan P, and Attia J (2009) Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl 32:131-139.
8. Hieronymus TL, Nanovskaya TN, Deshmukh SV, Vargas R, Hankins GD, and Ahmed MS (2006) Methadone metabolism by early gestational age placentas. Am J Perinatol 23:287-294.
9. Hollenberg PF, Kent UM, and Bumpus NN (2008) Mechanism-based inactivation of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications. Chem Res Toxicol 21:189-205.
10. Iribarne C, Dreano Y, Bardou LG, Menez JF, and Berthou F (1997) Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxoicology 117:13-23. (Pubitemid 27063996)
11. Jones DR, Gorski JC, Hamman MA, Mayhew BS, Rider S, and Hall SD (1999) Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther 290:1116-1125.
12. Kalgutkar AS, Obach RS, and Maurer TS (2007) Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr Drug Metab 8:407-447.
13. Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, and Hoffer C (2008) Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther 84:497-505.
14. Kharasch ED, Hoffer C, Whittington D, and Sheffels P (2004) Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther 76:250-269.
15. Kharasch ED, Hoffer C, Whittington D, Walker A, and Bedynek PS (2009) Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology 110:660-672.
16. Kim TW, Alford DP, Malabanan A, Holick MF, and Samet JH (2006) Low bone density in patients receiving methadone maintenance treatment. Drug Alcohol Depend 85:258-262.
17. Kleber HD (2008) Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA 300:2303-2305.
18. Krantz MJ, Kutinsky IB, Robertson AD, and Mehler PS (2003) Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 23:802-805.
19. Levine B, Wu SC, Dixon A, and Smialek JE (1995) Site dependence of postmortem blood methadone concentrations. Am J Forensic Med Pathol 16:97-100.
20. Morton EB (2007) Methadone Pharmacology. Ph.D. thesis, University of Adelaide, Adelaide, South Australia.
21. Nanovskaya TN, Deshmukh SV, Nekhayeva IA, Zharikova OL, Hankins GD, and Ahmed MS (2004) Methadone metabolism by human placenta. Biochem Pharmacol 68:583-591.
22. Ortiz de Montellano PR, Mico BA, Mathews JM, Kunze KL, Miwa GT, and Lu AY (1981) Selective inactivation of cytochrome P-450 isoenzymes by suicide substrates. Arch Biochem Biophys 210:717-728.
23. Osawa Y, Higashiyama T, Toma Y, and Yarborough C (1997) Diverse function of aromatase and the N-terminal sequence deleted form. J Steroid Biochem Mol Biol 61:117-126.
24. Pohland A, Boaz HE, and Sullivan HR (1971) Synthesis and identification of metabolites resulting from the biotransformation of DL-methadone in man and in the rat. J Med Chem 14:194-197.
25. Pond SM, Kreek MJ, Tong TG, Raghunath J, and Benowitz NL (1985) Altered methadone pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther 233:1-6. (Pubitemid 15083518)
26. Senay EC (1985) Methadone maintenance treatment. Int J Addict 20:803-821.
27. Serane VT and Kurian O (2008) Neonatal abstinence syndrome. Indian J Pediatr 75:911-914.
28. Shiran MR, Lennard MS, Iqbal MZ, Lagundoye O, Seivewright N, Tucker GT, and Rostami-Hodjegan A (2009) Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment. Br J Clin Pharmacol 67:29-37.
29. Silverman R (1988) Mechanism Based Inactivation: Chemistry and Enzymology. CRC Press, Boca Raton, FL.
30. Sims SA, Snow LA, and Porucznik CA (2007) Surveillance of methadone-related adverse drug events using multiple public health data sources. J Biomed Inform 40:382-389.
31. Szeto HH, Clapp JF 3rd, Larrow RW, Hewitt J, Inturrisi CE, and Mann LI (1981) Disposition of methadone in the ovine maternal-fetal unit. Life Sci 28:2111-2117.
32. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, and Kharasch ED (2008) Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology 108:363-374.
33. Wang JS and DeVane CL (2003) Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 31:742-747.
34. Weschules DJ, Bain KT, and Richeimer S (2008) Actual and potential drug interactions associated with methadone. Pain Med 9:315-344.
35. Wilkinson GR (2005) Drug metabolism and variability among patients in drug response. N Engl J Med 352:2211-2221.
36. Zharikova OL, Deshmukh SV, Nanovskaya TN, Hankins GD, and Ahmed MS (2006) The effect of methadone and buprenorphine on human placental aromatase. Biochem Pharmacol 71: 1255-1264.