Biotransformation of the antiretroviral drug etravirine: Metabolite identification, reaction phenotyping, and characterization of autoinduction of cytochrome P450-dependent metabolism

Drug Metabolism and Disposition

Volumn 40, Issue 4, 2012, Pages 803-814

  Yanakakis, Lindsay J ^a   Bumpus, Namandjé N ^b  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DRUG METABOLITE; ETRAVIRINE; GLUCURONOSYLTRANSFERASE 1A3; GLUCURONOSYLTRANSFERASE 1A8; MESSENGER RNA; SULFORAPHANE;

ALLELE; ARTICLE; CONTROLLED STUDY; CYP2C19 1 GENE; CYP2C19 2 GENE; DRUG METABOLISM; DRUG TRANSFORMATION; ENZYME INDUCTION; ENZYME MECHANISM; GENE; GENE EXPRESSION; GENE FUNCTION; GENE LOSS; GENOTYPE; HOMOZYGOTE; HUMAN; HUMAN CELL; HYDROGENATION; LIVER CELL; NUCLEOTIDE SEQUENCE; PHENOTYPE; PRIORITY JOURNAL;

ALLELES; ANTI-HIV AGENTS; ARYL HYDROCARBON HYDROXYLASES; BIOTRANSFORMATION; CELLS, CULTURED; CYTOCHROME P-450 CYP3A; DRUG INTERACTIONS; ENZYME INDUCTION; FEMALE; GLUCURONOSYLTRANSFERASE; HEPATOCYTES; HOMOZYGOTE; HUMANS; MALE; MICROSOMES, LIVER; MOLECULAR STRUCTURE; PREDICTIVE VALUE OF TESTS; PYRIDAZINES; REAL-TIME POLYMERASE CHAIN REACTION; RECEPTORS, STEROID; UP-REGULATION;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 84858394506     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.111.044404     Document Type: Article

References (33)

1. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R, et al. (2004) TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 48:4680-4686. (Pubitemid 39577672)
2. Calcagno A, Nozza S, Bonora S, Castagna A, Gonzalez de Requena D, D'Avolio A, Lazzarin A, and Di Perri G (2011) Pharmacokinetics of the raltegravir/maraviroc/etravirine combination. J Antimicrob Chemother 66:1932-1934.
3. de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, and Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419-15422.
4. Foti RS and Wahlstrom JL (2008) CYP2C19 inhibition: the impact of substrate probe selection on in vitro inhibition profiles. Drug Metab Dispos 36:523-528. (Pubitemid 351397977)
5. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK, et al. (2004) Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 292:191-201. (Pubitemid 38917996)
6. Götte M, Li X, and Wainberg MA (1999) HIV-1 reverse transcription: a brief overview focused on structure-function relationships among molecules involved in initiation of the reaction. Arch Biochem Biophys 365:199-210. (Pubitemid 29391627)
7. Gulick RM, Ribaudo HJ, Shikuma CM, Lalama C, Schackman BR, Meyer WA 3rd, Acosta EP, Schouten J, Squires KE, Pilcher CD, et al. (2006) Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA 296:769-781. (Pubitemid 44223101)
8. Gupta S, Vingerhoets J, Fransen S, Tambuyzer L, Azijn H, Frantzell A, Paredes R, Coakley E, Nijs S, Clotet B, et al. (2011) Connection domain mutations in HIV-1 reverse transcriptase do not impact etravirine susceptibility and virologic responses to etravirine-containing regimens. Antimicrob Agents Chemother 55:2872-2879.
9. Hyland R, Dickins M, Collins C, Jones H, and Jones B (2008) Maraviroc: in vitro assessment of drug-drug interaction potential. Br J Clin Pharmacol 66:498-507.
10. Kakuda TN, Abel S, Davis J, Hamlin J, Schöller-Gyüre M, Mack R, Ndongo N, Petit W, Ridgway C, Sekar V, et al. (2011) Pharmacokinetic interactions of maraviroc with darunavirritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials. Antimicrob Agents Chemother 55:2290-2296.
11. Kakuda TN, Wade JR, Snoeck E, Vis P, Schöller-Gyüre M, Peeters MP, Corbett C, Nijs S, Vingerhoets J, Leopold L, et al. (2010) Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther 88:695-703.
12. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, et al. (2007) Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 370:39-48. (Pubitemid 47017467)
13. Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, et al. (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795-804. (Pubitemid 34671092)
14. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, et al. (2007) Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, doubleblind, placebo-controlled trial. Lancet 370:29-38. (Pubitemid 47017466)
15. Nadler JP, Berger DS, Blick G, Cimoch PJ, Cohen CJ, Greenberg RN, Hicks CB, Hoetelmans RM, Iveson KJ, Jayaweera DS, et al. (2007) Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS 21:F1-F10. (Pubitemid 46568620)
16. Ozawa S, Soyama A, Saeki M, Fukushima-Uesaka H, Itoda M, Koyano S, Sai K, Ohno Y, Saito Y, and Sawada J (2004) Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet 19:83-95.
17. Parniak MA and Sluis-Cremer N (2000) Inhibitors of HIV-1 reverse transcriptase. Adv Pharmacol 49:67-109.
18. Picchio G, Vingerhoets J, Tambuyzer L, Coakley E, Haddad M, and Witek J (2011) Short communication: prevalence of susceptibility to etravirine by genotype and phenotype in samples received for routine HIV type 1 resistance testing in the United States. AIDS Res Hum Retroviruses 27:1271-1275.
19. Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, Garren KW, George T, Rooney JF, Brizz B, et al. (2008) Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358:2095-2106. (Pubitemid 351679596)
20. Schöller-Gyüre M, Kakuda TN, De Smedt G, Vanaken H, Bouche MP, Peeters M, Woodfall B, and Hoetelmans RM (2008) A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers. Br J Clin Pharmacol 66:508-516.
21. Schöller-Gyüre M, Kakuda TN, Raoof A, De Smedt G, and Hoetelmans RM (2009) Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet 48:561-574.
22. Song I, Borland J, Min S, Lou Y, Chen S, Patel P, Wajima T, and Piscitelli SC (2011) Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother 55:3517-3521.
23. Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, Delfraissy JF, Jemsek J, Rivero A, Rozenbaum W, Schrader S, et al. (2004) Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 36:1011-1019. (Pubitemid 38989366)
24. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DF, Farina D, et al. (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341:1865-1873.
25. Suzuki H, Kneller MB, Haining RL, Trager WF, and Rettie AE (2002) (+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19. Drug Metab Dispos 30:235-239. (Pubitemid 34175012)
26. Tibotec, Inc. (2011) Intelence (etravirine) full prescribing information. Tibotec, Inc., Beerse, Belgium.
27. Tolson AH, Li H, Eddington ND, and Wang H (2009) Methadone induces the expression of hepatic drug-metabolizing enzymes through the activation of pregnane X receptor and constitutive androstane receptor. Drug Metab Dispos 37:1887-1894.
28. Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, Andries K, Pauwels R, and de Béthune MP (2005) TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 79:12773-12782. (Pubitemid 41433197)
29. Walsky RL and Obach RS (2007) A comparison of 2-phenyl-2-(1-piperidinyl) propane (ppp), 1,1′,1″-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine as selective inactivators of human cytochrome P450 2B6. Drug Metab Dispos 35:2053-2059. (Pubitemid 350005195)
30. Wang H and LeCluyse EL (2003) Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 42:1331-1357. (Pubitemid 38045840)
31. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, and Desta Z (2003) The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287-300. (Pubitemid 36734384)
32. Willson TM and Kliewer SA (2002) PXR, CAR and drug metabolism. Nat Rev Drug Discov 1:259-266. (Pubitemid 37361442)
33. Zhou C, Poulton EJ, Grün F, Bammler TK, Blumberg B, Thummel KE, and Eaton DL (2007) The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Mol Pharmacol 71:220-229. (Pubitemid 46020992)