Skip to main content
SpringerLink
Log in

In Vitro Reaction Phenotyping and Drug Interaction Data

  • Chapter
  • First Online:
Book cover Pharmacokinetic and Pharmacodynamic Drug Interactions Associated with Antiretroviral Drugs

  • 465 Accesses

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

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  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):631–639

    CAS  PubMed  Google Scholar 

  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):381–388

    CAS  PubMed  Google Scholar 

  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):41–47

    CAS  PubMed  Google Scholar 

  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):287–300

    Article  CAS  PubMed  Google Scholar 

  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):1793–1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):45–50

    Article  CAS  PubMed  Google Scholar 

  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):1178–1182

    Article  CAS  PubMed  Google Scholar 

  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):851–860

    Article  CAS  PubMed  Google Scholar 

  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):803–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1488–1495

    CAS  PubMed  Google Scholar 

  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):5067–5079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):484–487

    Article  CAS  PubMed  Google Scholar 

  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):2855–2861

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Piliero PJ (2004) Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 37(Suppl 1):S2–S12

    Article  CAS  PubMed  Google Scholar 

  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):1165–1177

    Article  CAS  PubMed  Google Scholar 

  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):497–502

    CAS  PubMed  Google Scholar 

  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):1592–1596

    CAS  PubMed  PubMed Central  Google Scholar 

  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):267–276

    Article  CAS  PubMed  Google Scholar 

  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):757–766

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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):803–807

    Article  CAS  PubMed  Google Scholar 

  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):259–261

    Article  Google Scholar 

  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):307–314

    CAS  PubMed  Google Scholar 

  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):190–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):257–260

    CAS  PubMed  Google Scholar 

  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):1654–1658

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ernest CS 2nd, Hall SD, Jones DR (2005) Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther 312(2):583–591

    Article  CAS  PubMed  Google Scholar 

  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):1462–1467

    Article  CAS  PubMed  Google Scholar 

  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):609–616

    CAS  PubMed  Google Scholar 

  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):423–431

    CAS  PubMed  Google Scholar 

  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):207–217

    Article  PubMed  Google Scholar 

  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):1–17

    Article  CAS  PubMed  Google Scholar 

  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):79–85

    Article  CAS  PubMed  Google Scholar 

  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. 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):381–386

    Article  CAS  PubMed  Google Scholar 

  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):558–568

    Article  CAS  PubMed  Google Scholar 

  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):498–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):2221–2230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):353–361

    Article  CAS  PubMed  Google Scholar 

  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):1657–1663

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada

    Tony K. L. Kiang & Mary H. H. Ensom

  2. College of Pharmacy, Qatar University, Doha, Qatar

    Kyle John Wilby

Authors
  1. Tony K. L. Kiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyle John Wilby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary H. H. Ensom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary H. H. Ensom .

Editor information

Editors and Affiliations

  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Tony K. L. Kiang

  2. College of Pharmacy, Qatar University, Doha, Qatar

    Kyle John Wilby

  3. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Mary H. H. Ensom

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media Singapore

About this chapter

Cite this chapter

Kiang, T.K.L., Wilby, K.J., Ensom, M.H.H. (2016). In Vitro Reaction Phenotyping and Drug Interaction Data. In: Kiang, T., Wilby, K., Ensom, M. (eds) Pharmacokinetic and Pharmacodynamic Drug Interactions Associated with Antiretroviral Drugs. Adis, Singapore. https://doi.org/10.1007/978-981-10-2113-8_4

Download citation

Publish with us

Policies and ethics

Search

Navigation