Advertisement

In Vitro Reaction Phenotyping and Drug Interaction Data

  • Tony K. L. Kiang
  • Kyle John Wilby
  • Mary H. H. Ensom
Chapter

Abstract

This chapter summarizes the in vitro reaction phenotyping and drug interaction data for each antiretroviral agent. Investigations on the relative contributions of specific metabolizing enzymes and molecular enzyme inhibition/induction reactions will be presented for the following agents, based on drug class:
  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs): delavirdine, efavirenz, etravirine, nevirapine, and rilpivirine

  • Nucleoside reverse-transcriptase inhibitors (NRTIs): abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine

  • Protease inhibitors (PIs): atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, and lopinavir

  • Fusion inhibitors: enfuvirtide

  • Entry inhibitors: maraviroc

  • Integrase inhibitors: dolutegravir, elvitegravir, raltegravir

Keywords

CYP450 Enzyme Human Liver Microsome CYP3A4 Inhibition Integrase Inhibitor Primary Human Hepatocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Voorman RL, Maio SM, Hauer MJ, Sanders PE, Payne NA, Ackland MJ (1998) Metabolism of delavirdine, a human immunodeficiency virus type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species: probable involvement of CYP2D6 and CYP3A. Drug Metab Dispos 26(7):631–639PubMedGoogle Scholar
  2. 2.
    Voorman RL, Maio SM, Payne NA, Zhao Z, Koeplinger KA, Wang X (1998) Microsomal metabolism of delavirdine: evidence for mechanism-based inactivation of human cytochrome P450 3A. J Pharmacol Exp Ther 287(1):381–388PubMedGoogle Scholar
  3. 3.
    Voorman RL, Payne NA, Wienkers LC, Hauer MJ, Sanders PE (2001) Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6. Drug Metab Dispos 29(1):41–47PubMedGoogle Scholar
  4. 4.
    Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, 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(1):287–300CrossRefPubMedGoogle Scholar
  5. 5.
    Belanger AS, Caron P, Harvey M, Zimmerman PA, Mehlotra RK, Guillemette C (2009) Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dispos 37(9):1793–1796CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mugundu GM, Hariparsad N, Desai PB (2010) Impact of ritonavir, atazanavir and their combination on the CYP3A4 induction potential of efavirenz in primary human hepatocytes. Drug Metab Lett 4(1):45–50CrossRefPubMedGoogle Scholar
  7. 7.
    Keubler A, Weiss J, Haefeli WE, Mikus G, Burhenne J (2012) Drug interaction of efavirenz and midazolam: efavirenz activates the CYP3A-mediated midazolam 1′-hydroxylation in vitro. Drug Metab Dispos 40(6):1178–1182CrossRefPubMedGoogle Scholar
  8. 8.
    Ji HY, Lee H, Lim SR, Kim JH, Lee HS (2012) Effect of efavirenz on UDP-glucuronosyltransferase 1A1, 1A4, 1A6, and 1A9 activities in human liver microsomes. Molecules 17(1):851–860CrossRefPubMedGoogle Scholar
  9. 9.
    Yanakakis LJ, Bumpus NN (2012) Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping, and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metab Dispos 40(4):803–814CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Erickson DA, Mather G, Trager WF, Levy RH, Keirns JJ (1999) Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 27(12):1488–1495PubMedGoogle Scholar
  11. 11.
    Lade JM, Avery LB, Bumpus NN (2013) Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. Antimicrob Agents Chemother 57(10):5067–5079CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Weiss J, Haefeli WE (2013) Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. Int J Antimicrob Agents 41(5):484–487CrossRefPubMedGoogle Scholar
  13. 13.
    McDowell JA, Chittick GE, Ravitch JR, Polk RE, Kerkering TM, Stein DS (1999) Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study. Antimicrob Agents Chemother 43(12):2855–2861PubMedPubMedCentralGoogle Scholar
  14. 14.
    Piliero PJ (2004) Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 37(Suppl 1):S2–S12CrossRefPubMedGoogle Scholar
  15. 15.
    Nekvindova J, Masek V, Veinlichova A, Anzenbacherova E, Anzenbacher P, Zidek Z et al (2006) Inhibition of human liver microsomal cytochrome P450 activities by adefovir and tenofovir. Xenobiotica 36(12):1165–1177CrossRefPubMedGoogle Scholar
  16. 16.
    Barbier O, Turgeon D, Girard C, Green MD, Tephly TR, Hum DW et al (2000) 3′-azido-3′-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab Dispos 28(5):497–502PubMedGoogle Scholar
  17. 17.
    Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM (1998) Glucuronidation of 3′-azido-3′-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 42(7):1592–1596PubMedPubMedCentralGoogle Scholar
  18. 18.
    Eagling VA, Howe JL, Barry MJ, Back DJ (1994) The metabolism of zidovudine by human liver microsomes in vitro: formation of 3′-amino-3′-deoxythymidine. Biochem Pharmacol 48(2):267–276CrossRefPubMedGoogle Scholar
  19. 19.
    Pan-Zhou XR, Cretton-Scott E, Zhou XJ, Yang MX, Lasker JM, Sommadossi JP (1998) Role of human liver P450s and cytochrome b5 in the reductive metabolism of 3′-azido-3′-deoxythymidine (AZT) to 3′-amino-3′-deoxythymidine. Biochem Pharmacol 55(6):757–766CrossRefPubMedGoogle Scholar
  20. 20.
    Zheng J (2002) Clinical pharmacology and biopharmaceutics review (21–567). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-567_Reyataz_BioPharmr_P1.pdf. Accessed 6 June 2016
  21. 21.
    Arya V (2005) Clinical pharmacology and biopharmaceutics review (21–976). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021976s000_Sprycel_ClinPharmR.pdf. Accessed 6 June 2016
  22. 22.
    Decker CJ, Laitinen LM, Bridson GW, Raybuck SA, Tung RD, Chaturvedi PR (1998) Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 87(7):803–807CrossRefPubMedGoogle Scholar
  23. 23.
    von Moltke LL, Durol AL, Duan SX, Greenblatt DJ (2000) Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole. Eur J Clin Pharmacol 56(3):259–261CrossRefGoogle Scholar
  24. 24.
    Chiba M, Hensleigh M, Nishime JA, Balani SK, Lin JH (1996) Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 24(3):307–314PubMedGoogle Scholar
  25. 25.
    Eagling VA, Back DJ, Barry MG (1997) Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 44(2):190–194CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Iribarne C, Berthou F, Carlhant D, Dreano Y, Picart D, Lohezic F et al (1998) Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug Metab Dispos 26(3):257–260PubMedGoogle Scholar
  27. 27.
    Fayz S, Inaba T (1998) Zidovudine azido-reductase in human liver microsomes: activation by ethacrynic acid, dipyridamole, and indomethacin and inhibition by human immunodeficiency virus protease inhibitors. Antimicrob Agents Chemother 42(7):1654–1658PubMedPubMedCentralGoogle Scholar
  28. 28.
    Ernest CS 2nd, Hall SD, Jones DR (2005) Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther 312(2):583–591CrossRefPubMedGoogle Scholar
  29. 29.
    Hirani VN, Raucy JL, Lasker JM (2004) Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19. Drug Metab Dispos 32(12):1462–1467CrossRefPubMedGoogle Scholar
  30. 30.
    Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shetty BV et al (1998) Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 26(7):609–616PubMedGoogle Scholar
  31. 31.
    Kumar GN, Rodrigues AD, Buko AM, Denissen JF (1996) Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 277(1):423–431PubMedGoogle Scholar
  32. 32.
    Liu L, Mugundu GM, Kirby BJ, Samineni D, Desai PB, Unadkat JD (2012) Quantification of human hepatocyte cytochrome P450 enzymes and transporters induced by HIV protease inhibitors using newly validated LC-MS/MS cocktail assays and RT-PCR. Biopharm Drug Dispos 33(4):207–217CrossRefPubMedGoogle Scholar
  33. 33.
    Eagling VA, Wiltshire H, Whitcombe IW, Back DJ (2002) CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica 32(1):1–17CrossRefPubMedGoogle Scholar
  34. 34.
    Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT (2006) Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol 98(1):79–85CrossRefPubMedGoogle Scholar
  35. 35.
    Rajagopalan P (2000) Clinical pharmacology and biopharmaceutics reviews (21–226). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-226_Kaletra_biopharmr_P1.pdf. Accessed 6 June 2016
  36. 36.
    Weemhoff JL, von Moltke LL, Richert C, Hesse LM, Harmatz JS, Greenblatt DJ (2003) Apparent mechanism-based inhibition of human CYP3A in-vitro by lopinavir. J Pharm Pharmacol 55(3):381–386CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang X, Lalezari JP, Badley AD, Dorr A, Kolis SJ, Kinchelow T et al (2004) Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients. Clin Pharmacol Ther 75(6):558–568CrossRefPubMedGoogle Scholar
  38. 38.
    Hyland R, Dickins M, Collins C, Jones H, Jones B (2008) Maraviroc: in vitro assessment of drug-drug interaction potential. Br J Clin Pharmacol 66(4):498–507CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lu Y, Hendrix CW, Bumpus NN (2012) Cytochrome P450 3A5 plays a prominent role in the oxidative metabolism of the anti-human immunodeficiency virus drug maraviroc. Drug Metab Dispos 40(12):2221–2230CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Reese MJ, Savina PM, Generaux GT, Tracey H, Humphreys JE, Kanaoka E et al (2013) In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos 41(2):353–361CrossRefPubMedGoogle Scholar
  41. 41.
    Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K et al (2007) Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos 35(9):1657–1663CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2016

Authors and Affiliations

  • Tony K. L. Kiang
    • 1
  • Kyle John Wilby
    • 2
  • Mary H. H. Ensom
    • 1
  1. 1.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada
  2. 2.College of PharmacyQatar UniversityDohaQatar

Personalised recommendations