Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent Km of 4.21 mM and Vmax of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

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

Department of Obstetrics and Gynecology University Hospital Charles University Prague Hradec Kralove Czech Republic

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

Maternal and Fetal Health Research Centre Institute of Human Development University of Manchester St Mary's Hospital Central Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Science Centre Manchester United Kingdom

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UNAIDS. 2015. Fact sheet 2014. Global statistics 2014; UNAIDS, Geneva, Switzerland: http://www.unaids.org/en/media/unaids/contentassets/documents/factsheet/2014/20140716_FactSheet_en.pdf.

WHO. 2013. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. World Health Organization, Geneva, Switzerland. PubMed

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 2015. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf Accessed 26 May 2016.

Lamberth JR, Reddy SC, Pan JJ, Dasher KJ. 2015. Chronic hepatitis B infection in pregnancy. World J Hepatol 7:1233–1237. doi:10.4254/wjh.v7.i9.1233. PubMed DOI PMC

Wong F, Pai R, Van Schalkwyk J, Yoshida EM. 2014. Hepatitis B in pregnancy: a concise review of neonatal vertical transmission and antiviral prophylaxis. Ann Hepatol 13:187–195. PubMed

Benaboud S, Treluyer JM, Urien S, Blanche S, Bouazza N, Chappuy H, Rey E, Pannier E, Firtion G, Launay O, Hirt D. 2012. Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women. Antimicrob Agents Chemother 56:776–782. doi:10.1128/AAC.00370-11. PubMed DOI PMC

Staud F, Cerveny L, Ceckova M. 2012. Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. J Drug Target 20:736–763. doi:10.3109/1061186X.2012.716847. PubMed DOI

Ceckova-Novotna M, Pavek P, Staud F. 2006. P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod Toxicol 22:400–410. doi:10.1016/j.reprotox.2006.01.007. PubMed DOI

Hahnova-Cygalova L, Ceckova M, Staud F. 2011. Fetoprotective activity of breast cancer resistance protein (BCRP, ABCG2): expression and function throughout pregnancy. Drug Metab Rev 43:53–68. doi:10.3109/03602532.2010.512293. PubMed DOI

Meyer zu Schwabedissen HE, Jedlitschky G, Gratz M, Haenisch S, Linnemann K, Fusch C, Cascorbi I, Kroemer HK. 2005. Variable expression of MRP2 (ABCC2) in human placenta: influence of gestational age and cellular differentiation. Drug Metab Dispos 33:896–904. doi:10.1124/dmd.104.003335. PubMed DOI

Staud F, Cerveny L, Ahmadimoghaddam D, Ceckova M. 2013. Multidrug and toxin extrusion proteins (MATE/SLC47); role in pharmacokinetics. Int J Biochem Cell Biol 45:2007–2011. doi:10.1016/j.biocel.2013.06.022. PubMed DOI

Ahmadimoghaddam D, Hofman J, Zemankova L, Nachtigal P, Dolezelova E, Cerveny L, Ceckova M, Micuda S, Staud F. 2012. Synchronized activity of organic cation transporter 3 (Oct3/SLC22A3) and multidrug and toxin extrusion 1 (Mate1/SLC47A1) transporter in transplacental passage of MPP+ in rat. Toxicol Sci 128:471–481. doi:10.1093/toxsci/kfs160. PubMed DOI

Ahmadimoghaddam D, Zemankova L, Nachtigal P, Dolezelova E, Neumanova Z, Cerveny L, Ceckova M, Kacerovsky M, Micuda S, Staud F. 2013. Organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter in the placenta and fetal tissues: expression profile and fetus protective role at different stages of gestation. Biol Reprod 88:55. doi:10.1095/biolreprod.112.105064. PubMed DOI

Lee N, Hebert MF, Prasad B, Easterling TR, Kelly EJ, Unadkat JD, Wang J. 2013. Effect of gestational age on mRNA and protein expression of polyspecific organic cation transporters during pregnancy. Drug Metab Dispos 41:2225–2232. doi:10.1124/dmd.113.054072. PubMed DOI PMC

Terada T, Masuda S, Asaka J, Tsuda M, Katsura T, Inui K. 2006. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res 23:1696–1701. doi:10.1007/s11095-006-9016-3. PubMed DOI

Ahmadimoghaddam D, Staud F. 2013. Transfer of metformin across the rat placenta is mediated by organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) protein. Reprod Toxicol 39:17–22. doi:10.1016/j.reprotox.2013.03.001. PubMed DOI

Müller F, J König Hoier E, Mandery K, Fromm MF. 2013. 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 86:808–815. doi:10.1016/j.bcp.2013.07.008. PubMed DOI

Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, Clotet B, Pastor-Anglada M, Koepsell H, Martinez-Picado J. 2009. 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 329:252–261. doi:10.1124/jpet.108.146225. PubMed DOI

Jung N, Lehmann C, Rubbert A, Knispel M, Hartmann P, van Lunzen J, Stellbrink HJ, Faetkenheuer G, Taubert D. 2008. Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 36:1616–1623. doi:10.1124/dmd.108.020826. PubMed DOI

Sata R, Ohtani H, Tsujimoto M, Murakami H, Koyabu N, Nakamura T, Uchiumi T, Kuwano M, Nagata H, Tsukimori K, Nakano H, Sawada Y. 2005. Functional analysis of organic cation transporter 3 expressed in human placenta. J Pharmacol Exp Ther 315:888–895. doi:10.1124/jpet.105.086827. PubMed DOI

König J, Zolk O, Singer K, Hoffmann C, Fromm MF. 2011. Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations. Br J Pharmacol 163:546–555. doi:10.1111/j.1476-5381.2010.01052.x. PubMed DOI PMC

Müller F, König J, Glaeser H, Schmidt I, Zolk O, Fromm MF, Maas R. 2011. Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine. Antimicrob Agents Chemother 55:3091–3098. doi:10.1128/AAC.01835-10. PubMed DOI PMC

National Research Council. 1996. Guide for the care and use of laboratory animals. National Academies Press, Washington, DC.

Council of Europe. 1986. European convention for the protection of vertebrate animals used for experimental and other scientific purposes. European treaty series no. 123. Council of Europe, Strasbourg, France.

Neumanova Z, Cerveny L, Ceckova M, Staud F. 2014. Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta. AIDS 28:9–17. doi:10.1097/QAD.0000000000000112. PubMed DOI

Neumanova Z, Cerveny L, Greenwood SL, Ceckova M, Staud F. 2015. Effect of drug efflux transporters on placental transport of antiretroviral agent abacavir. Reprod Toxicol 57:176–182. doi:10.1016/j.reprotox.2015.07.070. PubMed DOI

Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. 2005. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A 102:17923–17928. doi:10.1073/pnas.0506483102. PubMed DOI PMC

Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM. 2013. Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem 56:781–795. doi:10.1021/jm301302s. PubMed DOI PMC

Dangprapai Y, Wright SH. 2011. Interaction of H+ with the extracellular and intracellular aspects of hMATE1. Am J Physiol Renal Physiol 301:F520–F528. doi:10.1152/ajprenal.00075.2011. PubMed DOI PMC

Astorga B, Ekins S, Morales M, Wright SH. 2012. Molecular determinants of ligand selectivity for the human multidrug and toxin extruder proteins MATE1 and MATE2-K. J Pharmacol Exp Ther 341:743–755. doi:10.1124/jpet.112.191577. PubMed DOI PMC

Tsuda M, Terada T, Asaka J, Ueba M, Katsura T, Inui K. 2007. Oppositely directed H+ gradient functions as a driving force of rat H+/organic cation antiporter MATE1. Am J Physiol Renal Physiol 292:F593–F598. PubMed

Staud F, Vackova Z, Pospechova K, Pavek P, Ceckova M, Libra A, Cygalova L, Nachtigal P, Fendrich Z. 2006. Expression and transport activity of breast cancer resistance protein (Bcrp/Abcg2) in dually perfused rat placenta and HRP-1 cell line. J Pharmacol Exp Ther 319:53–62. doi:10.1124/jpet.106.105023. PubMed DOI

Glazier JD, Jones CJ, Sibley CP. 1988. Purification and Na+ uptake by human placental microvillus membrane vesicles prepared by three different methods. Biochim Biophys Acta 945:127–134. doi:10.1016/0005-2736(88)90475-0. PubMed DOI

Glazier JD, Sibley CP. 2006. In vitro methods for studying human placental amino acid transport: placental plasma membrane vesicles. Methods Mol Med 122:241–252. PubMed

International Transporter Consortium, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. 2010. Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236. doi:10.1038/nrd3028. PubMed DOI PMC

Chappuy H, Treluyer JM, Jullien V, Dimet J, Rey E, Fouche M, Firtion G, Pons G, Mandelbrot L. 2004. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 48:4332–4336. doi:10.1128/AAC.48.11.4332-4336.2004. PubMed DOI PMC

Moodley D, Pillay K, Naidoo K, Moodley J, Johnson MA, Moore KH, Mudd PN Jr, Pakes GE. 2001. Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. J Clin Pharmacol 41:732–741. doi:10.1177/00912700122010636. PubMed DOI

Daud AN, Bergman JE, Bakker MK, Wang H, Kerstjens-Frederikse WS, de Walle HE, Groen H, Bos JH, Hak E, Wilffert B. 2015. P-glycoprotein-mediated drug interactions in pregnancy and changes in the risk of congenital anomalies: a case-reference study. Drug Saf 38:651–659. doi:10.1007/s40264-015-0299-3. PubMed DOI PMC

de Souza J, Benet LZ, Huang Y, Storpirtis S. 2009. Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK-MDR1, and Caco-2 cell monolayers. J Pharm Sci 98:4413–4419. doi:10.1002/jps.21744. PubMed DOI

Kim HS, Sunwoo YE, Ryu JY, Kang HJ, Jung HE, Song IS, Kim EY, Shim JC, Shon JH, Shin JG. 2007. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol 64:645–654. doi:10.1111/j.1365-2125.2007.02944.x. PubMed DOI PMC

Cygalova LH, Hofman J, Ceckova M, Staud F. 2009. Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility. J Pharmacol Exp Ther 331:1118–1125. doi:10.1124/jpet.109.160564. PubMed DOI

Watanabe S, Tsuda M, Terada T, Katsura T, Inui K. 2010. Reduced renal clearance of a zwitterionic substrate cephalexin in MATE1-deficient mice. J Pharmacol Exp Ther 334:651–656. doi:10.1124/jpet.110.169433. PubMed DOI

Mandelbrot L, Peytavin G, Firtion G, Farinotti R. 2001. Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol 184:153–158. doi:10.1067/mob.2001.108344. PubMed DOI

Aleksunes LM, Cui Y, Klaassen CD. 2008. Prominent expression of xenobiotic efflux transporters in mouse extraembryonic fetal membranes compared with placenta. Drug Metab Dispos 36:1960–1970. doi:10.1124/dmd.108.021337. PubMed DOI PMC

Lickteig AJ, Cheng X, Augustine LM, Klaassen CD, Cherrington NJ. 2008. Tissue distribution, ontogeny and induction of the transporters multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci 83:59–64. doi:10.1016/j.lfs.2008.05.004. PubMed DOI PMC

Balkovetz DF, Leibach FH, Mahesh VB, Devoe LD, Cragoe EJ Jr, Ganapathy V. 1986. Na+-H+ exchanger of human placental brush-border membrane: identification and characterization. Am J Physiol 251:C852–C860. PubMed

Ganapathy V, Balkovetz DF, Miyamoto Y, Ganapathy ME, Mahesh VB, Devoe LD, Leibach FH. 1986. Inhibition of human placental Na+-H+ exchanger by cimetidine. J Pharmacol Exp Ther 239:192–197. PubMed

Simon BJ, Kulanthaivel P, Burckhardt G, Ramamoorthy S, Leibach FH, Ganapathy V. 1992. Characterization of an ATP-driven H+ pump in human placental brush-border membrane vesicles. Biochem J 287:423–430. doi:10.1042/bj2870423. PubMed DOI PMC

Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB. 2010. Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol 298:F997–F1005. doi:10.1152/ajprenal.00431.2009. PubMed DOI

Cano-Soldado P, Lorrayoz IM, Molina-Arcas M, Casado FJ, Martinez-Picado J, Lostao MP, Pastor-Anglada M. 2004. Interaction of nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside transporter-1 (SLC28A1). Antivir Ther 9:993–1002. PubMed

Errasti-Murugarren E, Diaz P, Godoy V, Riquelme G, Pastor-Anglada M. 2011. Expression and distribution of nucleoside transporter proteins in the human syncytiotrophoblast. Mol Pharmacol 80:809–817. doi:10.1124/mol.111.071837. PubMed DOI

Molina-Arcas M, Casado FJ, Pastor-Anglada M. 2009. Nucleoside transporter proteins. Curr Vasc Pharmacol 7:426–434. doi:10.2174/157016109789043892. PubMed DOI

S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is Not a Selective Inhibitor of Equilibrative Nucleoside Transporters but Also Blocks Efflux Activity of Breast Cancer Resistance Protein

Efavirenz reduces renal excretion of lamivudine in rats by inhibiting organic cation transporters (OCT, Oct) and multidrug and toxin extrusion proteins (MATE, Mate)

MDR1 and BCRP Transporter-Mediated Drug-Drug Interaction between Rilpivirine and Abacavir and Effect on Intestinal Absorption