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Pathway Description
Lamivudine Metabolism Pathway
Homo sapiens
Drug Metabolism Pathway
Lamivudine (2'-deoxy-3'-thiacytidine, 3TC) is a pyrimidine analog reverse transcriptase enzyme inhibitor used to treat human immunodeficiency virus type I (HIV-1), HIV-2, and Hepatitis B. When metabolized to its active triphosphate form, it competes with deoxycytidine triphosphate for binding to reverse transcriptase, resulting in chain termination when incorporated into the viral DNA. Lamivudine may enter the cells by passive diffusion or by active transported via SLC22A1, SLC22A2, and SLC22A3. Intracellularly, it is phosphorylated to its active triphosphate from via deoxycytidine kinase (3TC to 3TC-monophosphate), followed by cytidine monophosphate/deoxycytidine monophosphate kinase (3TC-monophosphate to 3TC-diphosphate), then 3'-phosphoglycerate kinase or nucleoside diphosphate kinase (3TC-diphosphate to 3TC-triphosphate). Dephosphorylation can occur via phosphatases or salvage pathways. Lamivudine is actively transported out of cell by efflux transporters ABCB1, ABCC1, ABCC2, ABCC3, ABCC4 and ABCG2 and primarily excreted unchanged in the urine.
References
Lamivudine Pathway References
[PharmgKB](http://www.pharmgkb.org/pathway/PA165860384)
Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, Clotet B, Pastor-Anglada M, Koepsell H, Martinez-Picado J: 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 Apr;329(1):252-61. doi: 10.1124/jpet.108.146225. Epub 2009 Jan 13.
Pubmed: 19141712
Errasti-Murugarren E, Pastor-Anglada M: Drug transporter pharmacogenetics in nucleoside-based therapies. Pharmacogenomics. 2010 Jun;11(6):809-41. doi: 10.2217/pgs.10.70.
Pubmed: 20504255
Zhou Z, Rodman JH, Flynn PM, Robbins BL, Wilcox CK, D'Argenio DZ: Model for intracellular Lamivudine metabolism in peripheral blood mononuclear cells ex vivo and in human immunodeficiency virus type 1-infected adolescents. Antimicrob Agents Chemother. 2006 Aug;50(8):2686-94. doi: 10.1128/AAC.01637-05.
Pubmed: 16870759
Van Rompay AR, Johansson M, Karlsson A: Phosphorylation of nucleosides and nucleoside analogs by mammalian nucleoside monophosphate kinases. Pharmacol Ther. 2000 Aug-Sep;87(2-3):189-98.
Pubmed: 11008000
Cammack N, Rouse P, Marr CL, Reid PJ, Boehme RE, Coates JA, Penn CR, Cameron JM: Cellular metabolism of (-) enantiomeric 2'-deoxy-3'-thiacytidine. Biochem Pharmacol. 1992 May 28;43(10):2059-64.
Pubmed: 1318048
Hunsucker SA, Mitchell BS, Spychala J: The 5'-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther. 2005 Jul;107(1):1-30. doi: 10.1016/j.pharmthera.2005.01.003.
Pubmed: 15963349
Cihlar T, Ray AS: Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2010 Jan;85(1):39-58. doi: 10.1016/j.antiviral.2009.09.014. Epub 2009 Nov 1.
Pubmed: 19887088
Kim HS, Sunwoo YE, Ryu JY, Kang HJ, Jung HE, Song IS, Kim EY, Shim JC, Shon JH, Shin JG: The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol. 2007 Nov;64(5):645-54. doi: 10.1111/j.1365-2125.2007.02944.x. Epub 2007 May 17.
Pubmed: 17509035
Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV: Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study. J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):441-9. doi: 10.1097/01.qai.0000225013.53568.69.
Pubmed: 16791115
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 Metab Dispos. 2007 Mar;35(3):340-4. doi: 10.1124/dmd.106.012765. Epub 2006 Dec 15.
Pubmed: 17172311
Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama S, Baba M: Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003 Jan;63(1):65-72.
Pubmed: 12488537
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 Nov;98(11):4413-9. doi: 10.1002/jps.21744.
Pubmed: 19472342
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