Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir

Drug Metabolism and Disposition

Volumn 41, Issue 12, 2013, Pages 2166-2174

  Kharasch, Evan D ^a   Stubbert, Kristi ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALFENTANIL; CYTOCHROME P450 3A; FEXOFENADINE; LOPINAVIR PLUS RITONAVIR; METHADONE; MULTIDRUG RESISTANCE PROTEIN; ONDANSETRON;

ADULT; ARTICLE; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; CORRELATION ANALYSIS; DEMETHYLATION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DETERMINATION; DRUG DISPOSITION; DRUG EXPOSURE; DRUG ISOLATION; ENANTIOMER; ENZYME ACTIVITY; ENZYME INDUCTION; ENZYME INHIBITION; FEMALE; FIRST PASS EFFECT; HUMAN; HUMAN EXPERIMENT; INTESTINE ABSORPTION; KIDNEY CONCENTRATING CAPACITY; LIVER CLEARANCE; LIVER METABOLISM; MALE; MASS SPECTROMETRY; NAUSEA; NORMAL HUMAN; PRIORITY JOURNAL; PROTEIN INTERACTION; SINGLE DRUG DOSE; STEADY STATE; STEREOCHEMISTRY; VOMITING;

ADOLESCENT; ADULT; BIOLOGICAL AVAILABILITY; CYTOCHROME P-450 CYP3A; DRUG INTERACTIONS; FEMALE; HUMANS; INTESTINES; LIVER; LOPINAVIR; MALE; METHADONE; P-GLYCOPROTEIN; RITONAVIR; YOUNG ADULT;

EID: 84888633408     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.053991     Document Type: Article

References (60)

1. Bailey DG, Dresser GK, Leake BF, and Kim RB (2007) Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 81:495-502.
2. Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, Mayanja-Kizza H, Katabira E, Hanpithakpong W, Pakker N, Dorlo TP, Tarning J, and Lindegardh N, et al. (2012) Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother 67:1217-1223.
3. Chang Y, Fang WB, Lin SN, and Moody DE (2011) Stereo-selective metabolism of methadone by human liver microsomes and cDNA-expressed cytochrome P450s: a reconciliation. Basic Clin Pharmacol Toxicol 108:55-62.
4. Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, Donovan MI, Fishbain DA, Foley KM, and Fudin J, et al.; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel (2009) Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 10:113-130.
5. Clarke S, Mulcahy F, Bergin C, Reynolds H, Boyle N, Barry M, and Back DJ (2002) Absence of opioid withdrawal symptoms in patients receiving methadone and the protease inhibitor lopinavir-ritonavir. Clin Infect Dis 34:1143-1145.
6. Crettol S, Déglon JJ, Besson J, Croquette-Krokar M, Hämmig R, Gothuey I, Monnat M, and Eap CB (2006) ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 80:668-681.
7. Dickinson L, Khoo S, and Back D (2010) Pharmacokinetics and drug-drug interactions of anti-retrovirals: an update. Antiviral Res 85:176-189.
8. Ding R, Tayrouz Y, Riedel KD, Burhenne J, Weiss J, Mikus G, and Haefeli WE (2004) Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther 76:73-84.
9. Ferrari A, Coccia CP, Bertolini A, and Sternieri E (2004) Methadone - metabolism, pharmacokinetics and interactions. Pharmacol Res 50:551-559.
10. Foisy MM, Yakiwchuk EM, and Hughes CA (2008) Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 42:1048-1059.
11. 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.
12. Gerber JG, Rhodes RJ, and Gal J (2004) Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 16:36-44.
13. Greenblatt DJ, von Moltke LL, Daily JP, Harmatz JS, and Shader RI (1999) Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 19:293-296.
14. Griffin L, Annaert P, and Brouwer KL (2011) Influence of drug transport proteins on the pharmacokinetics and drug interactions of HIV protease inhibitors. J Pharm Sci 100:3636-3654.
15. Hogeland GW, Swindells S, McNabb JC, Kashuba AD, Yee GC, and Lindley CM (2007) Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther 81:69-75.
16. Hsu A, Granneman GR, and Bertz RJ (1998) Ritonavir: clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 35:275-291.
17. Iribarne C, Berthou F, Baird S, Dréano Y, Picart D, Bail JP, Beaune P, and Ménez JF (1996) Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 9:365-373.
18. Khalsa JH and Elkashef A (2010) Drug interactions between antiretroviral medications and medications used in the treatment of drug addiction: research needs. Am J Addict 19:96-100.
19. Kharasch ED (2011) Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesth Analg 112:13-16.
20. Kharasch ED, Bedynek PS, Hoffer C, Walker A, and Whittington D (2012a) Lack of indinavir effects on methadone disposition despite inhibition of hepatic and intestinal cytochrome P4503A (CYP3A). Anesthesiology 116:432-447.
21. Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, and Hoffer C (2008a) Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther 84:497-505.
22. Kharasch ED, Bedynek PS, Walker A, Whittington D, and Hoffer C (2008b) Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities. Clin Pharmacol Ther 84:506-512.
23. Kharasch ED, Francis A, London A, Frey K, Kim T, and Blood J (2011a) Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther 90:100-108.
24. Kharasch ED, Hoffer C, Whittington D, and Sheffels P (2004a) 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.
25. Kharasch ED, Hoffer C, Whittington D, Walker A, and Bedynek PS (2009a) Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology 110:660-672.
26. Kharasch ED, Mitchell D, Coles R, and Blanco R (2008c) Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother 52:1663-1669.
27. Kharasch ED and Stubbert K (2013) Role of cytochrome P4502B6 in methadone metabolism and clearance. J Clin Pharmacol 53:305-313.
28. Kharasch ED, Vangveravong S, Buck N, London A, Kim T, Blood J, and Mach RH (2011b) Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil. Clin Pharmacol Ther 89:562-570.
29. Kharasch ED, Walker A, Hoffer C, and Sheffels P (2004b) Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther 76:452-466.
30. Kharasch ED, Walker A, Hoffer C, and Sheffels P (2005) Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination. J Clin Pharmacol 45:79-88.
31. Kharasch ED, Walker A, Isoherranen N, Hoffer C, Sheffels P, Thummel K, Whittington D, and Ensign D (2007) Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam. Clin Pharmacol Ther 82:410-426.
32. Kharasch ED, Walker A, Whittington D, Hoffer C, and Bedynek PS (2009b) Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug Alcohol Depend 101:158-168.
33. Kharasch ED, Whittington D, Ensign D, Hoffer C, Bedynek PS, Campbell S, Stubbert K, Crafford A, London A, and Kim T (2012b) Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 91:673-684.
34. Kirby BJ, Collier AC, Kharasch ED, Dixit V, Desai P, Whittington D, Thummel KE, and Unadkat JD (2011a) Complex drug interactions of HIV protease inhibitors 2: in vivo induction and in vitro to in vivo correlation of induction of cytochrome P450 1A2, 2B6, and 2C9 by ritonavir or nelfinavir. Drug Metab Dispos 39:2329-2337.
35. Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, and Unadkat JD (2011b) Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos 39:1070-1078.
36. Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, and Unadkat JD (2012) Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab Dispos 40:610-616.
37. Levran O, Peles E, Hamon S, Randesi M, Adelson M, and Kreek MJ (2013) CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction. Addict Biol 18:709-716.
38. Lin HL, D'Agostino J, Kenaan C, Calinski D, and Hollenberg PF (2013) The effect of ritonavir on human CYP2B6 catalytic activity: heme modification contributes to the mechanism-based inactivation of CYP2B6 and CYP3A4 by ritonavir. Drug Metab Dispos 41:1813-1824.
39. Lobmaier P, Gossop M, Waal H, and Bramness J (2010) The pharmacological treatment of opioid addiction - a clinical perspective. Eur J Clin Pharmacol 66:537-545.
40. Lüthi B, Huttner A, Speck RF, and Mueller NJ (2007) Methadone-induced torsade de pointes after stopping lopinavir-ritonavir. Eur J Clin Microbiol Infect Dis 26:367-369.
41. Matsushima S, Maeda K, Hayashi H, Debori Y, Schinkel AH, Schuetz JD, Kusuhara H, and Sugiyama Y (2008) Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol 73:1474-1483.
42. McCance-Katz EF, Rainey PM, Friedland G, and Jatlow P (2003) The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. Clin Infect Dis 37:476-482.
43. McCance-Katz EF, Sullivan LE, and Nallani S (2010) Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict 19:4-16.
44. Nicholson AB (2007) Methadone for cancer pain. Cochrane Database Syst Rev (4):CD003971.
45. Ortega I, Rodriguez M, Suarez E, Perez-Ruixo JJ, and Calvo R (2007) Modeling methadone pharmacokinetics in rats in presence of P-glycoprotein inhibitor valspodar. Pharm Res 24:1299-1308.
46. Pal D, Kwatra D, Minocha M, Paturi DK, Budda B, and Mitra AK (2011) Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. Life Sci 88:959-971.
47. Piscitelli SC, Kress DR, Bertz RJ, Pau A, and Davey R (2000) The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine. Pharmacotherapy 20:549-553.
48. Saber-Tehrani AS, Bruce RD, and Altice FL (2011) Pharmacokinetic drug interactions and adverse consequences between psychotropic medications and pharmacotherapy for the treatment of opioid dependence. Am J Drug Alcohol Abuse 37:1-11.
49. 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.
50. 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.
51. Stevens RC, Rapaport S, Maroldo-Connelly L, Patterson JB, and Bertz R (2003) Lack of methadone dose alterations or withdrawal symptoms during therapy with lopinavir/ritonavir. J Acquir Immune Defic Syndr 33:650-651.
52. Svärd J, Spiers JP, Mulcahy F, and Hennessy M (2010) Nuclear receptor-mediated induction of CYP450 by antiretrovirals: functional consequences of NR1I2 (PXR) polymorphisms and differential prevalence in whites and sub-Saharan Africans. J Acquir Immune Defic Syndr 55:536-549.
53. Totah RA, Allen KE, Sheffels P, Whittington D, and Kharasch ED (2007) Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther 321:389-399.
54. 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.
55. van Heeswijk RP, Bourbeau M, Campbell P, Seguin I, Chauhan BM, Foster BC, and Cameron DW (2006) Time-dependent interaction between lopinavir/ritonavir and fexofenadine. J Clin Pharmacol 46:758-767.
56. Vishnuvardhan D, Moltke LL, Richert C, and Greenblatt DJ (2003) Lopinavir: acute exposure inhibits P-glycoprotein; extended exposure induces P-glycoprotein. AIDS 17:1092-1094.
57. Wang SC, Ho IK, Tsou HH, Tian JN, Hsiao CF, Chen CH, Tan HK, Lin L, Wu CS, and Su LW, et al. (2011) CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol 31:463-469.
58. Webster LR (2005) Methadone-related deaths. J Opioid Manag 1:211-217.
59. Wyen C, Fuhr U, Frank D, Aarnoutse RE, Klaassen T, Lazar A, Seeringer A, Doroshyenko O, Kirchheiner JC, and Abdulrazik F, et al. (2008) Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Ther 84:75-82.
60. Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ, Jr, Klein CE, Rublein JC, and Kashuba AD (2006) Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 42:52-60.