Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor used in first-line combination antiretroviral therapy (cART). It is usually administered with nucleoside reverse transcriptase inhibitors (NRTI), many of which are substrates of OCT uptake solute carriers (SLC22A) and MATE (SLC47A), P-gp (MDR1, ABCB1), BCRP (ABCG2), or MRP2 (ABCC2) efflux transporters. The aim of this study was to evaluate the inhibitory potential of efavirenz towards these transporters and investigate its effects on the pharmacokinetics and tissue distribution of a known Oct/Mate substrate, lamivudine, in rats. Accumulation and transport assays showed that efavirenz inhibits the uptake of metformin by OCT1-, OCT2- and MATE1-expressing MDCK cells and reduces transcellular transport of lamivudine across OCT1/OCT2- and MATE1-expressing MDCK monolayers. Only negligible inhibition of MATE2-K was observed in HEK-MATE2-K cells. Efavirenz also reduced the efflux of calcein from MDCK-MRP2 cells, but had a rather weak inhibitory effect on Hoechst 33342 accumulation in MDCK-MDR1 and MDCK-BCRP cells. An in vivo pharmacokinetic interaction study in male Wistar rats revealed that intravenous injection of efavirenz or the control Oct/Mate inhibitor cimetidine significantly reduced the recovery of lamivudine in urine and greatly increased lamivudine retention in the renal tissue. Co-administration with efavirenz or cimetidine also increased the AUC0-∞ value and reduced total body clearance of lamivudine. These data suggest that efavirenz is a potent inhibitor of OCT/Oct and MATE/Mate transporters. Consequently, it can engage in drug-drug interactions that reduce renal excretion of co-administered substrates and enhance their retention in the kidneys, potentially compromising therapeutic safety.

Department of Pharmacology and Toxicology Charles University Prague Faculty of Pharmacy in Hradec Kralove Hradec Kralove Czech Republic

Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Zobrazit více v PubMed

AIDSinfo. Panel on Antiretroviral Guidelines for Adults and Adolescents Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services; [Online] 2017. [cited [Accessed on 12/27/2017] ].

WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach– 2nd Edition. 2016. PubMed

Mouton JP, Cohen K, Maartens G. Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen. Expert Rev Clin Pharmacol. 2016;9(11):1493–503. 10.1080/17512433.2016.1221760 . PubMed DOI

Wondifraw Baynes H, Tegene B, Gebremichael M, Birhane G, Kedir W, Biadgo B. Assessment of the effect of antiretroviral therapy on renal and liver functions among HIV-infected patients: a retrospective study. HIV AIDS (Auckl). 2017;9:1–7. 10.2147/HIV.S120979 ; PubMed Central PMCID: PMCPMC5191837. PubMed DOI PMC

Bednasz CJ, Venuto CS, Ma Q, Morse GD. Pharmacokinetic Considerations for Combining Antiretroviral Therapy, Direct-Acting Antiviral Agents for Hepatitis C Virus, and Addiction Treatment Medications. Clin Pharmacol Drug Dev. 2017;6(2):135–9. 10.1002/cpdd.313 ; PubMed Central PMCID: PMCPMC5341144. PubMed DOI PMC

Kis O, Robillard K, Chan GN, Bendayan R. The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci. 2010;31(1):22–35. 10.1016/j.tips.2009.10.001 . PubMed DOI

DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol. 2012;52:249–73. 10.1146/annurev-pharmtox-010611-134529 . PubMed DOI

Zolk O, Fromm MF. Transporter-mediated drug uptake and efflux: important determinants of adverse drug reactions. Clin Pharmacol Ther. 2011;89(6):798–805. 10.1038/clpt.2010.354 . PubMed DOI

Gorboulev V, Ulzheimer JC, Akhoundova A, UlzheimerTeuber I, Karbach U, Quester S, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA and Cell Biology. 1997;16(7):871–81. 10.1089/dna.1997.16.871 PubMed PMID: WOS:A1997XQ08200007. PubMed DOI

Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(50):17923–8. 10.1073/pnas.0506483102 PubMed PMID: WOS:000234010500010. PubMed DOI PMC

EMA. Committee for Human Medicinal Products: Concept paper on a revision of the Guideline on the 4 investigation of drug interactions. 2017;(EMEA/CHMP/694687/2016):23 March 2017.

FDA. Guidance for industry, drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations Clinical Pharmacology. Silver Spring (MD): FDA; 2012.

Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM. Highlights from the International Transporter Consortium second workshop. Clin Pharmacol Ther. 2012;92(5):553–6. 10.1038/clpt.2012.126 . PubMed DOI

Dirson G, Fernandez C, Hindlet P, Roux F, German-Fattal M, Gimenez F, et al. Efavirenz does not interact with the ABCB1 transporter at the blood-brain barrier. Pharm Res. 2006;23(7):1525–32. 10.1007/s11095-006-0279-5 . PubMed DOI

Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochemical Pharmacology. 2007;73(10):1573–81. 10.1016/j.bcp.2007.01.027 PubMed PMID: WOS:000246091200007. PubMed DOI

Stormer E, von Moltke LL, Perloff MD, Greenblatt DJ. Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture. Pharm Res. 2002;19(7):1038–45. . PubMed

Zelena L, Reznicek J, Ceckova M, Sklenarova H. Universal efavirenz determination in transport study, rat placenta perfusion and placenta lysate by HPLC-UV. J Pharm Biomed Anal. 2017;137:70–7. 10.1016/j.jpba.2017.01.012 . PubMed DOI

Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE. Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. Drug Metabolism and Disposition. 2007;35(3):340–4. 10.1124/dmd.106.012765 PubMed PMID: WOS:000244484200005. PubMed DOI

Weiss J, Rose J, Storch CH, Ketabi-Kiyanvash N, Sauer A, Haefeli WE, et al. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. Journal of Antimicrobial Chemotherapy. 2007;59(2):238–45. 10.1093/jac/dkl474 PubMed PMID: WOS:000245011800011. PubMed DOI

Jung N, Lehmann C, Rubbert A, Knispel M, Hartmann P, van Lunzen J, et al. Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metabolism and Disposition. 2008;36(8):1616–23. 10.1124/dmd.108.020826 PubMed PMID: WOS:000257829900022. PubMed DOI

Moss DM, Liptrott NJ, Siccardi M, Owen A. Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter. Front Pharmacol. 2015;6:78 10.3389/fphar.2015.00078 ; PubMed Central PMCID: PMCPMC4392609. PubMed DOI PMC

Moore KH, Yuen GJ, Raasch RH, Eron JJ, Martin D, Mydlow PK, et al. Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin Pharmacol Ther. 1996;59(5):550–8. 10.1016/S0009-9236(96)90183-6 . PubMed DOI

Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, et al. Transport of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J Pharmacol Exp Ther. 2009;329(1):252–61. 10.1124/jpet.108.146225 . PubMed DOI

Müller F, Konig J, Hoier E, Mandery K, Fromm MF. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol. 2013;86(6):808–15. 10.1016/j.bcp.2013.07.008 . PubMed DOI

Ceckova M, Reznicek J, Ptackova Z, Cerveny L, Muller F, Kacerovsky M, et al. Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine. Antimicrob Agents Chemother. 2016;60(9):5563–72. 10.1128/AAC.00648-16 ; PubMed Central PMCID: PMCPMC4997848. PubMed DOI PMC

König J, Zolk O, Singer K, Hoffmann C, Fromm MF. Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations. Br J Pharmacol. 2011;163(3):546–55. 10.1111/j.1476-5381.2010.01052.x ; PubMed Central PMCID: PMCPMC3101617. PubMed DOI PMC

National Research Council (U.S.). Committee for the Update of the Guide for the Care and Use of Laboratory Animals., Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.). Guide for the care and use of laboratory animals 8th ed Washington, D.C.: National Academies Press; 2011. xxv, 220 p. p.

Council of Europe. Explanatory report on the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes Strasbourg, Croton, N.Y: The Council; Manhattan Pub. Co; distributor; 1986. 75 p. p.

Muller F, Pontones CA, Renner B, Mieth M, Hoier E, Auge D, et al. N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction. Eur J Clin Pharmacol. 2015;71(1):85–94. Epub 2015/01/02. 10.1007/s00228-014-1770-2 . PubMed DOI

Marzolini C, Telenti A, Decosterd L, Biollaz J, Buclin T. 'Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients'. Aids. 2001;15(9):1193–4. 10.1097/00002030-200106150-00023 PubMed PMID: WOS:000169319400023. PubMed DOI

Adedoyin A, Aarons L, Houston JB. Dose-dependent pharmacokinetics of cimetidine in the rat. Xenobiotica. 1987;17(5):595–604. . PubMed

Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H, et al. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther. 2012;340(2):393–403. 10.1124/jpet.111.184986 . PubMed DOI

Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther. 2009;329(1):185–91. 10.1124/jpet.108.147918 . PubMed DOI

Kido Y, Matsson P, Giacomini KM. Profiling of a Prescription Drug Library for Potential Renal Drug-Drug Interactions Mediated by the Organic Cation Transporter 2. Journal of Medicinal Chemistry. 2011;54(13):4548–58. 10.1021/jm2001629 PubMed PMID: WOS:000292479600018. PubMed DOI PMC

Takubo T, Kato T, Kinami J, Hanada K, Ogata H. Uptake of lamivudine by rat renal brush border membrane vesicles. J Pharm Pharmacol. 2002;54(1):111–7. . PubMed

Takubo T, Kato T, Kinami J, Hanada K, Ogata H. Effect of trimethoprim on the renal clearance of lamivudine in rats. J Pharm Pharmacol. 2000;52(3):315–20. . PubMed

Johnson MA, Moore KH, Yuen GJ, Bye A, Pakes GE. Clinical pharmacokinetics of lamivudine. Clin Pharmacokinet. 1999;36(1):41–66. 10.2165/00003088-199936010-00004 . PubMed DOI

Tweedie D, Polli JW, Berglund EG, Huang SM, Zhang L, Poirier A, et al. Transporter studies in drug development: experience to date and follow-up on decision trees from the International Transporter Consortium. Clin Pharmacol Ther. 2013;94(1):113–25. 10.1038/clpt.2013.77 . PubMed DOI

Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, et al. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther. 2013;94(1):52–63. 10.1038/clpt.2013.74 . PubMed DOI

Stahle L, Moberg L, Svensson JO, Sonnerborg A. Efavirenz plasma concentrations in HIV-infected patients: inter- and intraindividual variability and clinical effects. Ther Drug Monit. 2004;26(3):267–70. . PubMed

Almond LM, Hoggard PG, Edirisinghe D, Khoo SH, Back DJ. Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals. J Antimicrob Chemother. 2005;56(4):738–44. 10.1093/jac/dki308 . PubMed DOI

Kim HS, Sunwoo YE, Ryu JY, Kang HJ, Jung HE, Song IS, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol. 2007;64(5):645–54. 10.1111/j.1365-2125.2007.02944.x ; PubMed Central PMCID: PMCPMC2203270. PubMed DOI PMC

de Souza J, Benet LZ, Huang Y, Storpirtis S. Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK-MDR1, and Caco-2 cell monolayers. J Pharm Sci. 2009;98(11):4413–9. 10.1002/jps.21744 . PubMed DOI

Company B-MS. Sustiva Prescribing Information. 2015;March.

Said SM, Nasr SH, Samsa R, Markowitz GS, D'Agati VD. Nephrotoxicity of antiretroviral therapy in an HIV-infected patient. Kidney International. 2007;71(10):1071–5. 10.1038/sj.ki.5002134 PubMed PMID: WOS:000246721900020. PubMed DOI

Morris AAM, Baudouin S, Snow MH. Renal tubular acidosis and hypophosphataemia after treatment with nucleoside reverse transcriptase inhibitors. Aids. 2001;15(1):140–1. 10.1097/00002030-200101050-00027 PubMed PMID: WOS:000166230600031. PubMed DOI

Maggi P, Montinaro V, Bellacosa C, Pietanza S, Volpe A, Graziano G, et al. Early markers of tubular dysfunction in antiretroviral-experienced HIV-infected patients treated with tenofovir versus abacavir. AIDS Patient Care STDS. 2012;26(1):5–11. 10.1089/apc.2011.0185 . PubMed DOI

Reznicek J, Ceckova M, Cerveny L, Muller F, Staud F. Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters. Xenobiotica. 2017;47(1):77–85. 10.3109/00498254.2016.1158886 . PubMed DOI