Chapter 17 : Metabolism of Antiviral Nucleosides and Nucleotides

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Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy against human immunodeficiency virus (HIV), herpesviruses (including herpes simplex virus type 1 [HSV-1], HSV-2, varicella-zoster virus, and cytomegalovirus), and the hepatitis B and C viruses (HBV and HCV, respectively). Rather than providing a comprehensive discussion of the metabolism of individual agents, this chapter gives a general overview of enzymes involved in the metabolism of nucleoside and nucleotide analogs. It also highlights a few examples illustrating the unique pharmacology of the molecules. Competing with anabolism, various modes of catabolism and egress can serve to limit the maximal and temporal levels of the active species in target cells. Antiviral nucleoside and nucleotide analogs represent a large structural diversity with analogs mimicking virtually all the natural ribose and 2'-deoxyribose nucleosides and nucleotides. The importance of the 3' hydroxyl in the interaction of nucleosides with nucleoside transporters may differentiate the distribution of 3'-deoxynucleoside analogs and 3'-hydroxyl-containing nucleoside analogs. Anion and cation transporters with more general substrate specificity have also been identified to interact with nucleosides and nucleotides. In addition to anabolic drug interactions, highly catabolized nucleosides can have their levels altered due to interference with their degradation pathways. Drug interactions due to changes in elimination have also been observed to occur between nucleoside and nucleotide analogs and concomitant agents not related to nucleosides. Successful prodrug strategies promise to more effectively target infected tissues while decreasing exposure to sites of toxicity, offering the potential to increase efficacy while decreasing unwanted side effects.

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 1.
Figure 1.

Structural diversity of antiviral nucleoside analogs. The structures of the clinically used antiherpes nucleoside brivudin, anti-HCV nucleoside ribavirin, anti-HBV nucleoside entecavir, and the anti-HIV nucleosides zidovudine, stavudine, and emtricitabine (in the absence of the 5-fluoro substitution lamivudine).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 2.
Figure 2.

Generic pathways for the permeation, anabolism, and catabolism of nucleoside analogs. Nucleoside analogs can enter the cell through passive diffusion or solute carrier protein-mediated facilitated diffusion (FD), exchange (Ex), or cotrans-port (CT). Once in the cell, nucleoside analogs can be sequentially phosphorylated by nucleoside kinases (NK), NMP kinases (NMPK), and NDP kinases (NDPKs) to their respective NMP, NDP, and NTP analog forms. Nucleoside analogs can be eliminated by catabolic process or effluxed from the cell by ATP binding cassette transporters (ABC).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 3.
Figure 3.

Mechanism of renal active tubular secretion of the acyclic nucleotide phosphonate tenofovir that is used in the treatment of HIV and under investigation as a therapy for HBV. Tenofovir is transported from the blood into urine by the combined action of basolateral influx and apical efflux pumps. At the basolateral membrane tenofovir is a better substrate for the organic anion transporter 1 (OAT1) than for OAT3 and is not transported by the organic cation transporters 1 and 2 (OCT1 and OCT2) ( ). At the apical membrane tenofovir is transported by the multidrug-resistance-related protein 4 (MRP4) and is not transported by the breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or MRP2 ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 4.
Figure 4.

Anabolism of the antiherpes drug acyclovir. The first phosphorylation step is efficiently catalyzed by thymidine kinases (TK) of herpesviruses including HSV-1, HSV-2, and varicella-zoster virus ( ). Acyclovir is also inefficiently phos-phorylated by IMP phosphotransferase ( ). The second phosphorylation step is carried out by cellular guanylate kinase ( ). Seven enzymes can catalyze the third phosphorylation step to the active NTP species (in order of efficiency, as follows: phosphoglycerate kinase ≫ pyruvate kinase > phosphoenolpyruvate carboxykinase > nucleoside diphosphate kinase > succinylcoenzyme A synthetase > creatine kinase > adenylsuccinate synthetase) ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 5.
Figure 5.

Metabolism of 2´-deoxy-2´-fluoro-2´-C-methylcytidine (2´F-2´CMeC) including formation of 2´-deoxy-2´-fluoro-2´-C-methyluridine (2´F-2´CMeU) and its nucleotide metabolites. 2´F-2´CMeC can be phosphorylated sequentially by deoxycyti-dine kinase (dCK), uridylate-cytidylate kinase (UMP-CMP kinase), and NDP kinase (NDPK). 2´F-2´CMeC can also be deaminated by cytidine deaminase to 2´F-2´CMeU, which is not phosphorylated. Deamination by 2´-deoxycytidylate deaminase yields 2´F-2´CMeUMP, which can be phosphorylated by the same pathway as the cytidine nucleotide analog. The scheme summarizes results from prior reports ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 6.
Figure 6.

Anabolism and catabolism of the anti-HIV drug didanosine (ddI). The first phosphorylation step for ddI is catalyzed by IMP phosphotransferase ( ). The anabolic pathway of ddIMP then overlaps with the de novo synthesis pathway generating ATP including conversion to an AMP analog by adenylsuccinate synthase and lyase and phosphorylation by adenylate kinase and creatine kinase to form the antiviral active metabolite 2´,3´-dideoxyadenosine-TP (ddATP) ( ). ddI is extensively catabolized by a pathway including depurination catalyzed by purine nucleoside phosphorylase (PNP) followed by further metabolism to uric acid by xanthine oxidase (XOD) ( ). Putative sites for the drug interactions resulting in increased exposure to ddI are shown including inhibition of PNP by the phosphorylated metabolites of tenofovir and ganciclovir (GCV) and inhibition of XOD by allopurinol and its metabolite oxypurinol. Figure reprinted from reference with permission ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 7.

Cidofovir is an acyclic phosphonate analog of 2´-deoxycytidine and does not require the action of a nucleoside kinase for its two-step activation pathway. Cidofovir is first phosphorylated by uridylate-cytidylate kinase (UMP-CMP kinase). Three enzymes can catalyze the second phosphorylation step to the active NTP analog (in order of efficiency as follows: pyruvate kinase > NDP kinase > creatinine kinase). Cidofovir-MP is not a substrate of phosphoglycerate kinase or succinyl-coenzyme A synthetase) ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 8.
Figure 8.

The two major catabolic routes for abacavir are oxidation mediated by alcohol dehydrogenase and conjugation mediated by UDP-glucuronosyltransferase. Human radiolabeled balanced excretion studies have identified the 5´-glucuronide and 5´-carboxylic acid as accounting for 30 and 36% of the dose, respectively ( ). During formation of the 5´-carboxylic acid, the first oxidation step catalyzed by alcohol dehydrogenase and double-bond isomerization have led to the proposal of formation of a reactive Michael acceptor potentially able to form covalent adducts. The metabolic scheme is based on the catabolism of abacavir and the carbocyclic guanosine analog carbovir in vitro ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Image of Figure 9.
Figure 9.

Structures of nucleoside and nucleotide prodrugs. Famciclovir is the orally bioavailable prodrug of penciclovir in clinical use for herpes. NM 283 and R1626 are prodrugs meant to increase the oral exposure to the experimental anti-HCV nucleosides 2´-C-methylcytidine and 4´-azidocytidine ( ). Adefovir dipivoxil and tenofovir disoproxil are prodrugs that increase the oral bioavailability of the acyclic nucleotide phosphonates adefovir and tenofovir and are used clinically for HBV and HIV therapy, respectively ( ). MB06866 (also known as pradefovir) is an alternate prodrug of adefovir targeted to the liver by cytochrome P450-mediated degradation ( ). GS 9131 is a lymphoid targeted prodrug of a ribose modified nucleotide phosphonate being assessed as an anti-HIV agent ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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1. Acosta, E. P.,, L. M. Page, and, C. V. Fletcher. 1996. Clinical pharmacokinetics of zidovudine. An update. Clin. Pharmacokinet. 30:251262.
2. Ahluwalia, G.,, D. A. Cooney,, L. L. Bondoc, Jr.,, M. J. Currens,, H. Ford,, D. G. Johns,, H. Mitsuya, and, A. Fridland. 1990. Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the antiviral nucleoside 2´, 3´-dideoxyguanosine. Biochem. Biophys. Res. Commun. 171:12971303.
3. Ahluwalia, G.,, D. A. Cooney,, H. Mitsuya,, A. Fridland,, K. P. Flora,, Z. Hao,, M. Dalal,, S. Broder, and, D. G. Johns. 1987. Initial studies on the cellular pharmacology of 2´, 3´-dideoxyinosine, an inhibitor of HIV infectivity. Biochem. Pharmacol. 36:37973800.
4. Anderson, P. L.,, T. N. Kakuda, and, K. A. Lichtenstein. 2004. The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin. Infect. Dis. 38:743753.
5. Arner, E. S., and, S. Eriksson. 1995. Mammalian deoxyribonucleoside kinases. Pharmacol. Ther. 67:155186.
6. Balimane, P. V., and, P. J. Sinko. 1999. Involvement of multiple transporters in the oral absorption of nucleoside analogues. Adv. Drug Deliv. Rev. 39:183209.
7. Balzarini, J. 2000. Effect of antimetabolite drugs of nucleotide metabolism on the anti-human immunodeficiency virus activity of nucleoside reverse transcriptase inhibitors. Pharmacol. Ther. 87:175187.
8. Balzarini, J.,, L. Naesens,, M. J. Robins, and, E. De Clercq. 1990. Potentiating effect of ribavirin on the in vitro and in vivo antiretrovirus activities of 2´, 3´-dideoxyinosine and 2´, 3´-dideoxy-2, 6-diaminopurine riboside. J. Acquir. Immune Defic. Syndr. 3:11401147.
9. Balzarini, J.,, R. Pauwels,, M. Baba,, P. Herdewijn,, E. de Clercq,, S. Broder, and, D. G. Johns. 1988. The in vitro and in vivo anti-retrovirus activity, and intracellular metabolism of 3´-azido-2´, 3´-dideoxythymidine and 2´, 3´-dideoxycytidine are highly dependent on the cell species. Biochem. Pharmacol. 37:897903.
10. Barditch-Crovo, P.,, J. Toole,, C. W. Hendrix,, K. C. Cundy,, D. Ebeling,, H. S. Jaffe, and, P. S. Lietman. 1997. Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-infected patients. J. Infect. Dis. 176:406413.
11. Benzaria, S.,, C. Pierra,, D. Bardiot,, E. Cretton-Scott,, E. G. Bridges,, X. J. Zhou,, D. Standring, and, G. Gosselin. 2003. Monoval-LdC: efficient prodrug of 2´-deoxy-beta-L-cytidine (L-dC), a potent and selective anti-HBV agent. Nucleosides Nucleotides Nucleic Acids 22:10031006.
12. Blum, M. R.,, S. H. Liao, and, P. de Miranda. 1982. Overview of acyclovir pharmacokinetic disposition in adults and children. Am. J. Med. 73:186192.
13. Borst, P.,, J. Balzarini,, N. Ono,, G. Reid,, H. de Vries,, P. Wielinga,, J. Wijnholds, and, N. Zelcer. 2004. The potential impact of drug transporters on nucleoside-analog-based antiviral chemotherapy. Antivir. Res. 62:17.
14. Bourdais, J.,, R. Biondi,, S. Sarfati,, C. Guerreiro,, I. Lascu,, J. Janin, and, M. Veron. 1996. Cellular phosphorylation of anti-HIV nucleosides. Role of nucleoside diphosphate kinase. J. Biol. Chem. 271:78877890.
15. Burger, D. M.,, P. L. Meenhorst,, C. H. Koks, and, J. H. Beijnen. 1993. Pharmacokinetic interaction between rifampin and zidovu-dine. Antimicrob. Agents Chemother. 37:14261431.
16. Cass, C. E.,, J. D. Young,, S. A. Baldwin,, M. A. Cabrita,, K. A. Graham,, M. Griffiths,, L. L. Jennings,, J. R. Mackey,, A. M. Ng,, M. W. Ritzel,, M. F. Vickers, and, S. Y. Yao. 1999. Nucleoside transporters of mammalian cells. Pharm. Biotechnol. 12:313352.
17. Chang, C.,, P. W. Swaan,, L. Y. Ngo,, P. Y. Lum,, S. D. Patil, and, J. D. Unadkat. 2004. Molecular requirements of the human nucleoside transporters hCNT1, hCNT2, and hENT1. Mol. Pharmacol. 65:558570.
18. Chen, C. H., and, Y. C. Cheng. 1992. The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2´, 3´-dideoxycytidine. J. Biol. Chem. 267:28562859.
19. Cheng, Y. C.,, G. Dutschman,, E. De Clercq,, A. S. Jones,, S. G. Rahim,, G. Verhelst, and, R. T. Walker. 1981. Differential affinities of 5-(2-halogenovinyl)-2´-deoxyuridines for deoxythymidine kinases of various origins. Mol. Pharmacol. 20:230233.
20. Cihlar, T., and, M. S. Chen. 1996. Identification of enzymes catalyzing two-step phosphorylation of cidofovir and the effect of cytomegalovirus infection on their activities in host cells. Mol. Pharmacol. 50:15021510.
21. Cihlar, T.,, E. S. Ho,, D. C. Lin, and, A. S. Mulato. 2001. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 20:641648.
22. Cihlar, T.,, A. S. Ray,, C. Boojamra,, L. Zhang,, H. Hui,, D. Grant,, K. L. White,, M. Desai,, N. Parkin, and, R. Mackman. 2006. GS9148: a novel nucleotide active against HIV-1 variants resistant with drug-resistance mutations in reverse transcriptase, abstr. 45. Abstr. 13th Conference on Retrovirus and Opportunistic Infections.
23. Clarke, S. E.,, A. W. Harrell, and, R. J. Chenery. 1995. Role of aldehyde oxidase in the in vitro conversion of famciclovir to penciclovir in human liver. Drug Metab. Dispos. 23:251254.
24. Clay, P. G. 2002. The abacavir hypersensitivity reaction: a review. Clin. Ther. 24:15021514.
25. Cohen, S. S. 1977. The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA). Cancer 40:509518.
26. Cooney, D. A.,, M. Dalal,, H. Mitsuya,, J. B. McMahon,, M. Nadkarni,, J. Balzarini,, S. Broder, and, D. G. Johns. 1986. Initial studies on the cellular pharmacology of 2´, 3-dideoxycytidine, an inhibitor of HTLV-III infectivity. Biochem. Pharmacol. 35:20652068.
27. Cretton, E. M., and, J. P. Sommadossi. 1993. Reduction of 3´-azido-2´, 3´-dideoxynucleosides to their 3´-amino metabolite is mediated by cytochrome P-450 and NADPH-cytochrome P-450 reductase in rat liver microsomes. Drug Metab. Dispos. 21:946950.
28. Cretton, E. M.,, Z. Zhou,, L. B. Kidd,, H. M. McClure,, S. Kaul,, M. J. Hitchcock, and, J. P. Sommadossi. 1993. In vitro and in vivo disposition and metabolism of 3´-deoxy-2´, 3´-didehydrothymi-dine. Antimicrob. Agents Chemother. 37:18161825.
29. Cundy, K. C.,, P. Barditch-Crovo,, R. E. Walker,, A. C. Collier,, D. Ebeling,, J. Toole, and, H. S. Jaffe. 1995. Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrob. Agents Chemother. 39:24012405.
30. Cundy, K. C.,, J. A. Fishback,, J. P. Shaw,, M. L. Lee,, K. F. Soike,, G. C. Visor, and, W. A. Lee. 1994. Oral bioavailability of the anti-retroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from three formulations of the prodrug bis(pivaloyloxymethyl)-PMEA in fasted male cynomolgus monkeys. Pharm. Res. 11:839843.
31. Cundy, K. C.,, Z. H. Li, and, W. A. Lee. 1996. Effect of probenecid on the distribution, metabolism, and excretion of cidofovir in rabbits. Drug Metab. Dispos. 24:315321.
32. Cundy, K. C.,, B. G. Petty,, J. Flaherty,, P. E. Fisher,, M. A. Polis,, M. Wachsman,, P. S. Lietman,, J. P. Lalezari,, M. J. Hitchcock, and, H. S. Jaffe. 1995. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 39:12471252.
33. Cundy, K. C.,, C. Sueoka,, G. R. Lynch,, L. Griffin,, W. A. Lee, and, J. P. Shaw. 1998. Pharmacokinetics and bioavailability of the anti-human immunodeficiency virus nucleotide analog 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs. Antimicrob. Agents Chemother. 42:687690.
34. De Clercq, E., and, H. J. Field. 2006. Antiviral prodrugs—the development of successful prodrug strategies for antiviral chemo-therapy. Br. J. Pharmacol. 147:111.
35. Descamps, J., and, E. De Clercq. 1981. Specific phosphorylation of E-5-(2-iodovinyl)-2´-deoxyuridine by herpes simplex virus-infected cells. J. Biol. Chem. 256:59735976.
36. Di Bisceglie, A. M.,, M. Shindo,, T. L. Fong,, M. W. Fried,, M. G. Swain,, N. V. Bergasa,, C. A. Axiotis,, J. G. Waggoner,, Y. Park, and, J. H. Hoofnagle. 1992. A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 16:649654.
37. Dolce, V.,, G. Fiermonte,, M. J. Runswick,, F. Palmieri, and, J. E. Walker. 2001. The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. Proc. Natl. Acad. Sci. USA 98:22842288.
38. Eagling, V. A.,, J. L. Howe,, M. J. Barry, and, D. J. Back. 1994. The metabolism of zidovudine by human liver microsomes in vitro: formation of 3´-amino-3´-deoxythymidine. Biochem. Pharmacol. 48:267276.
39. Elion, G. B. 1993. Acyclovir: discovery, mechanism of action, and selectivity. J. Med. Virol. 1993(Suppl. 1):26.
40. Elion, G. B.,, P. A. Furman,, J. A. Fyfe,, P. de Miranda,, L. Beauchamp, and, H. J. Schaeffer. 1977. Selectivity of action of an anti-herpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc. Natl. Acad. Sci. USA 74:57165720.
41. Erion, M. D.,, P. D. van Poelje,, D. A. Mackenna,, T. J. Colby,, A. C. Montag,, J. M. Fujitaki,, D. L. Linemeyer, and, D. A. Bullough. 2005. Liver-targeted drug delivery using HepDirect prodrugs. J. Pharmacol. Exp. Ther. 312:554560.
42. Faletto, M. B.,, W. H. Miller,, E. P. Garvey,, M. H. St Clair,, S. M. Daluge, and, S. S. Good. 1997. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob. Agents Chemother. 41:10991107.
43. Feng, J. Y.,, W. B. Parker,, M. L. Krajewski,, D. Deville-Bonne,, M. Veron,, P. Krishnan,, Y. C. Cheng, and, K. Borroto-Esoda. 2004. Anabolism of amdoxovir: phosphorylation of dioxolane guano-sine and its 5´-phosphates by mammalian phosphotransferases. Biochem. Pharmacol. 68:18791888.
44. Field, A. K.,, M. E. Davies,, C. DeWitt,, H. C. Perry,, R. Liou,, J. Germershausen,, J. D. Karkas,, W. T. Ashton,, D. B. Johnston, and, R. L. Tolman. 1983. 9-([2-hydroxy-1-(hydroxymethyl)ethoxy] methyl)guanine: a selective inhibitor of herpes group virus replication. Proc. Natl. Acad. Sci. USA 80:41394143.
45. Fisher, E. J.,, K. Chaloner,, D. L. Cohn,, L. B. Grant,, B. Alston,, C. L. Brosgart,, B. Schmetter,, W. M. El-Sadr, and, J. Sampson. 2001. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial. AIDS 15:16951700.
46. Fukami-Kobayashi, K.,, M. Nosaka,, A. Nakazawa, and, M. Go. 1996. Ancient divergence of long and short isoforms of adenylate kinase: molecular evolution of the nucleoside monophosphate kinase family. FEBS Lett. 385:214220.
47. Furman, P. A.,, P. de Miranda,, M. H. St Clair, and, G. B. Elion. 1981. Metabolism of acyclovir in virus-infected and uninfected cells. Antimicrob. Agents Chemother. 20:518524.
48. Furman, P. A.,, J. A. Fyfe,, M. H. St Clair,, K. Weinhold,, J. L. Ride-out,, G. A. Freeman,, S. N. Lehrman,, D. P. Bolognesi,, S. Broder,, H. Mitsuya, et al. 1986. Phosphorylation of 3´-azido-3´-deoxythymidine and selective interaction of the 5´-triphosphate with human immunodeficiency virus reverse transcriptase. Proc. Natl. Acad. Sci. USA 83:83338337.
49. Fyfe, J. A.,, P. M. Keller,, P. A. Furman,, R. L. Miller, and, G. B. Elion. 1978. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl) guanine. J. Biol. Chem. 253:87218727.
50. Ganapathy, M. E.,, W. Huang,, H. Wang,, V. Ganapathy, and, F. H. Leibach. 1998. Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem. Biophys. Res. Commun. 246:470475.
51. Gao, W. Y.,, R. Agbaria,, J. S. Driscoll, and, H. Mitsuya. 1994. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2´, 3´-dideoxynucleoside analogs in resting and activated human cells. J. Biol. Chem. 269:1263312638.
52. Hadziyannis, S. J.,, N. C. Tassopoulos,, E. J. Heathcote,, T. T. Chang,, G. Kitis,, M. Rizzetto,, P. Marcellin,, S. G. Lim,, Z. Goodman,, M. S. Wulfsohn,, S. Xiong,, J. Fry, and, C. L. Brosgart. 2003. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N. Engl. J. Med. 348:800807.
53. Hantz, O.,, C. Perigaud,, C. Borel,, C. Jamard,, F. Zoulim,, C. Trepo,, J. L. Imbach, and, G. Gosselin. 1999. The SATE pronucleotide approach applied to acyclovir. Part II. Effects of bis(SATE) phosphotriester derivatives of acyclovir on duck hepatitis B virus replication in vitro and in vivo. Antivir. Res. 40:179187.
54. Hartman, N. R.,, G. S. Ahluwalia,, D. A. Cooney,, H. Mitsuya,, S. Kageyama,, A. Fridland,, S. Broder, and, D. G. Johns. 1991. Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the anti-human immunodeficiency virus nucleosides 2´, 3´-dideoxyadenosine and 2´, 3´-dideoxyinosine. Mol. Pharmacol. 40:118124.
55. Harvie, P.,, R. F. Omar,, N. Dusserre,, N. Lansac,, A. Desormeaux,, P. Gourde,, M. Simard,, M. Tremblay,, D. Beauchamp, and, M. G. Bergeron. 1996. Ribavirin potentiates the efficacy and toxicity of 2´, 3´-dideoxyinosine in the murine acquired immunodeficiency syndrome model. J. Pharmacol. Exp. Ther. 279:10091017.
56. Havlir, D. V.,, C. Tierney,, G. H. Friedland,, R. B. Pollard,, L. Smeaton,, J. P. Sommadossi,, L. Fox,, H. Kessler,, K. H. Fife, and, D. D. Richman. 2000. In vivo antagonism with zidovudine plus stavu-dine combination therapy. J. Infect. Dis. 182:321325.
57. Hedaya, M. A., and, R. J. Sawchuk. 1989. Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit. J. Pharm. Sci. 78:716722.
58. Hediger, M. A.,, M. F. Romero,, J. B. Peng,, A. Rolfs,, H. Takanaga, and, E. A. Bruford. 2004. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Pflugers Arch. 447:465468.
59. Hernandez-Santiago, B.,, L. Placidi,, E. Cretton-Scott,, A. Faraj,, E. G. Bridges,, M. L. Bryant,, J. Rodriguez-Orengo,, J. L. Imbach,, G. Gosselin,, C. Pierra,, D. Dukhan, and, J. P. Sommadossi. 2002. Pharmacology of beta-L-thymidine and beta-L-2´-deoxycytidine in HepG2 cells and primary human hepatocytes: relevance to chemotherapeutic efficacy against hepatitis B virus. Antimicrob. Agents Chemother. 46:17281733.
60. Ho, E. S.,, D. C. Lin,, D. B. Mendel, and, T. Cihlar. 2000. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J. Am. Soc. Nephrol. 11:383393.
61. Ho, H. T., and, M. J. Hitchcock. 1989. Cellular pharmacology of 2´, 3´-dideoxy-2´, 3´-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob. Agents Chemother. 33:844849.
62. Hoggard, P. G., and, D. J. Back. 2002. Intracellular pharmacology of nucleoside analogues and protease inhibitors: role of transporter molecules. Curr. Opin. Infect. Dis. 15:38.
63. Holy, A. 2003. Phosphonomethoxyalkyl analogs of nucleotides. Curr. Pharm. Des. 9:25672592.
64. Ibrahim, S. S., and, F. D. Boudinot. 1991. Pharmacokinetics of 2´, 3´-dideoxycytidine after high-dose administration to rats. J. Pharm. Sci. 80:3638.
65. Imaoka, T.,, H. Kusuhara,, M. Adachi,, J. D. Schuetz,, K. Takeuchi, and, Y. Sugiyama. 2007. Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol. Pharmacol. 71:619627.
66. Jarvis, S. M.,, J. A. Thorn, and, P. Glue. 1998. Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioino-sine-sensitive (es)-nucleoside transporters. Br. J. Pharmacol. 123:15871592.
67. Johansson, N. G., and, S. Eriksson. 1996. Structure-activity relationships for phosphorylation of nucleoside analogs to monophosphates by nucleoside kinases. Acta Biochim. Pol. 43:143160.
68. Johnson, A. A.,, A. S. Ray,, J. Hanes,, Z. Suo,, J. M. Colacino,, K. S. Anderson, and, K. A. Johnson. 2001. Toxicity of antiviral nucleo-side analogs and the human mitochondrial DNA polymerase. J. Biol. Chem. 276:4084740857.
69. Johnson, M. A., and, A. Fridland. 1989. Phosphorylation of 2´, 3´-dideoxyinosine by cytosolic 5´-nucleotidase of human lymphoid cells. Mol. Pharmacol. 36:291295.
70. Jones, R. J., and, N. Bischofberger. 1995. Minireview: nucleotide prodrugs. Antivir. Res. 27:117.
71. Jung, D., and, A. Dorr. 1999. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J. Clin. Pharmacol. 39:800804.
72. Kaul, S.,, W. C. Shyu,, U. A. Shukla,, K. A. Dandekar, and, R. H. Barbhaiya. 1993. Absorption, disposition, and metabolism of [14C]didanosine in the beagle dog. Drug Metab. Dispos. 21:447453.
73. Keller, P. M.,, S. A. McKee, and, J. A. Fyfe. 1985. Cytoplasmic 5´-nucleotidase catalyzes acyclovir phosphorylation. J. Biol. Chem. 260:86648667.
74. Kelley, J. A.,, C. L. Litterst,, J. S. Roth,, D. T. Vistica,, D. G. Poplack,, D. A. Cooney,, M. Nadkarni,, F. M. Balis,, S. Broder, and, D. G. Johns. 1987. The disposition and metabolism of 2´, 3´-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. Drug Metab. Dispos. 15:595601.
75. Koepsell, H., and, H. Endou. 2004. The SLC22 drug transporter family. Pflugers Arch. 447:666676.
76. Krishnan, P.,, Q. Fu,, W. Lam,, J. Y. Liou,, G. Dutschman, and, Y. C. Cheng. 2002. Phosphorylation of pyrimidine deoxynucleoside analog diphosphates: selective phosphorylation of L-nucleoside analog diphosphates by 3-phosphoglycerate kinase. J. Biol. Chem. 277:54535459.
77. Lalezari, J. P.,, R. J. Stagg,, B. D. Kuppermann,, G. N. Holland,, F. Kramer,, D. V. Ives,, M. Youle,, M. R. Robinson,, W. L. Drew, and, H. S. Jaffe. 1997. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann. Intern. Med. 126:257263.
78. Larsson, A.,, K. Stenberg,, A. C. Ericson,, U. Haglund,, W. A. Yisak,, N. G. Johansson,, B. Oberg, and, R. Datema. 1986. Mode of action, toxicity, pharmacokinetics, and efficacy of some new anti-herpesvirus guanosine analogs related to buciclovir. Antimicrob. Agents Chemother. 30:598605.
79. Laskin, O. L.,, J. A. Longstreth,, C. C. Hart,, D. Scavuzzo,, C. M. Kalman,, J. D. Connor, and, R. B. Roberts. 1987. Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome. Clin. Pharmacol. Ther. 41:546555.
80. Lee, W. A.,, G. X. He,, E. Eisenberg,, T. Cihlar,, S. Swaminathan,, A. Mulato, and, K. C. Cundy. 2005. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob. Agents Chemother. 49:18981906.
81. Lee, W. A., and, J. C. Martin. 2006. Perspectives on the development of acyclic nucleotide analogs as antiviral drugs. Antivir. Res. 71:254259.
82. Li, F.,, H. Maag, and, T. Alfredson. 2008. Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J. Pharm. Sci. 97:11091134.
83. Lim, S. E., and, W. C. Copeland. 2001. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J. Biol. Chem. 276:2361623623.
84. Ma, H.,, W. R. Jiang,, N. Robledo,, V. Leveque,, S. Ali,, T. Lara-Jaime,, M. Masjedizadeh,, D. B. Smith,, N. Cammack,, K. Klumpp, and, J. Symons. 2007. Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2´-deoxy-2´-fluoro-2´-C-methylcytidine (PSI-6130) and identification of a novel active 5-triphosphate species. J. Biol. Chem. 282:2981229820.
85. Mahony, W. B.,, B. A. Domin,, R. T. McConnell, and, T. P. Zimmerman. 1988. Acyclovir transport into human erythrocytes. J. Biol. Chem. 263:92859291.
86. Marcellin, P.,, T. T. Chang,, S. G. Lim,, M. J. Tong,, W. Sievert,, M. L. Shiffman,, L. Jeffers,, Z. Goodman,, M. S. Wulfsohn,, S. Xiong,, J. Fry, and, C. L. Brosgart. 2003. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N. Engl. J. Med. 348:808816.
87. Margot, N. A., and, M. D. Miller. 2005. In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1. Antivir. Ther. 10:343348.
88. Matthews, S. J. 2006. Entecavir for the treatment of chronic hepatitis B virus infection. Clin. Ther. 28:184203.
89. McDowell, J. A.,, G. E. Chittick,, J. R. Ravitch,, R. E. Polk,, T. M. Kerkering, and, D. S. Stein. 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. 43:28552861.
90. McDowell, J. A.,, G. E. Chittick,, C. P. Stevens,, K. D. Edwards, and, D. S. Stein. 2000. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob. Agents Chemother. 44:16861690.
91. McGuigan, C.,, D. Cahard,, H. M. Sheeka,, E. De Clercq, and, J. Balzarini. 1996. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. J. Med. Chem. 39:17481753.
92. McGuigan, C.,, S. A. Harris,, S. M. Daluge,, K. S. Gudmundsson,, E. W. McLean,, T. C. Burnette,, H. Marr,, R. Hazen,, L. D. Condreay,, L. Johnson,, E. De Clercq, and, J. Balzarini. 2005. Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency. J. Med. Chem. 48:35043515.
93. McGuigan, C.,, R. N. Pathirana,, N. Mahmood,, K. G. Devine, and, A. J. Hay. 1992. Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT. Antivir. Res. 17:311321.
94. McKee, E. E.,, A. T. Bentley,, M. Hatch,, J. Gingerich, and, D. Susan-Resiga. 2004. Phosphorylation of thymidine and AZT in heart mitochondria: elucidation of a novel mechanism of AZT cardiotoxicity. Cardiovasc. Toxicol. 4:155167.
95. Miller, W. H., and, R. L. Miller. 1980. Phosphorylation of acyclovir (acycloguanosine) monophosphate by GMP kinase. J. Biol. Chem. 255:72047207.
96. Miller, W. H., and, R. L. Miller. 1982. Phosphorylation of acyclovir diphosphate by cellular enzymes. Biochem. Pharmacol. 31:38793884.
97. Moreno, A.,, C. Quereda,, L. Moreno,, M. J. Perez-Elias,, A. Muriel,, J. L. Casado,, A. Antela,, F. Dronda,, E. Navas,, R. Barcena, and, S. Moreno. 2004. High rate of didanosine-related mitochondrial toxicity in HIV/HCV-coinfected patients receiving ribavirin. Antivir. Ther. 9:133138.
98. Murakami, E.,, H. Bao,, M. Ramesh,, T. R. McBrayer,, T. Whitaker,, H. M. Micolochick Steuer,, R. F. Schinazi,, L. J. Stuyver,, A. Obikhod,, M. J. Otto, and, P. A. Furman. 2007. Mechanism of activation of beta-D-2´-deoxy-2´-fluoro-2´-c-methylcytidine and inhibition of hepatitis C virus NS5B RNA polymerase. Antimicrob. Agents Chemother. 51:503509.
99. Murakami, E.,, C. Niu,, H. Bao,, H. M. Micolochick Steuer,, M. J. Otto, and, P. A. Furman. 2007. The mechanism of action of b-D-2´-deoxy-2´-fluoro-2´-C-methylcytidine involves a second metabolic pathway leading to b-D-2´-deoxy=2´=fluoro-2´-cmethyluridine 5´-triphosphate, a potent inhibitor of the HCV RNA-dependent RNA polymerase, abstr. P-262. Abstr. 14th Int. Symp. Hepatitis C Virus Related Viruses.
100. Okuda, H.,, K. Ogura,, A. Kato,, H. Takubo, and, T. Watabe. 1998. A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. J. Pharmacol. Exp. Ther. 287:791799.
101. Olsen, D. B.,, A. B. Eldrup,, L. Bartholomew,, B. Bhat,, M. R. Bosserman,, A. Ceccacci,, L. F. Colwell,, J. F. Fay,, O. A. Flores,, K. L. Getty,, J. A. Grobler,, R. L. LaFemina,, E. J. Markel,, G. Migliaccio,, M. Prhavc,, M. W. Stahlhut,, J. E. Tomassini,, M. MacCoss,, D. J. Hazuda, and, S. S. Carroll. 2004. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother. 48:39443953.
102. Painter, G. R.,, M. R. Almond,, L. C. Trost,, B. M. Lampert,, J. Neyts,, E. De Clercq,, B. E. Korba,, K. A. Aldern,, J. R. Beadle, and, K. Y. Hostetler. 2007. Evaluation of hexadecyloxypropyl-9-R-[2-(phosphonomethoxy)propyl]-adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections. Antimicrob. Agents Chemother. 51:35053509.
103. Pan, G.,, N. Giri, and, W. F. Elmquist. 2007. Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine. Drug Metab. Dispos. 35:11651173.
104. Parker, W. B. 2005. Metabolism and antiviral activity of ribavirin. Virus Res. 107:165171.
105. Patanella, J. E., and, J. S. Walsh. 1992. Oxidation of carbovir, a carbocyclic nucleoside, by rat liver cytosolic enzymes. Enantioselectivity and enantiomeric inhibition. Drug Metab. Dispos. 20:912919.
106. Pecora Fulco, P., and, M. A. Kirian. 2003. Effect of tenofovir on didanosine absorption in patients with HIV. Ann. Pharmacother. 37:13251328.
107. Perigaud, C.,, G. Gosselin,, J. L. Girardet,, B. E. Korba, and, J. L. Imbach. 1999. The S-acyl-2-thioethyl pronucleotide approach applied to acyclovir. Part I. Synthesis and in vitro anti-hepatitis B virus activity of bis(S-acyl-2-thioethyl)phosphotriester derivatives of acyclovir. Antivir. Res. 40:167178.
108. Perkins, E. S.,, R. M. Wood,, M. L. Sears,, W. H. Prusoff, and, A. D. Welch. 1962. Anti-viral activities of several iodinated pyrimidine deoxyribonucleosides. Nature 194:985986.
109. Pierra, C.,, A. Amador,, S. Benzaria,, E. Cretton-Scott,, M. D’Amours,, J. Mao,, S. Mathieu,, A. Moussa,, E. G. Bridges,, D. N. Standring,, J. P. Sommadossi,, R. Storer, and, G. Gosselin. 2006. Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2´-C-methylcytidine. J. Med. Chem. 49:66146620.
110. Piliero, P. J. 2004. Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors. J. Acquir. Immune Defic. Syndr. 37:S2S12.
111. Ray, A. S. 2005. Intracellular interactions between nucleos(t)ide inhibitors of HIV reverse transcriptase. AIDS Rev. 7:113125.
112. Ray, A. S.,, T. Cihlar,, K. L. Robinson,, L. Tong,, J. E. Vela,, M. D. Fuller,, L. M. Wieman,, E. J. Eisenberg, and, G. R. Rhodes. 2006. Mechanism of active renal tubular efflux of tenofovir. Antimicrob. Agents Chemother. 50:32973304.
113. Ray, A. S.,, L. Olson, and, A. Fridland. 2004. Role of purine nucleoside phosphorylase in interactions between 2´, 3´-dideoxyinosine and allopurinol, ganciclovir, or tenofovir. Antimicrob. Agents Chemother. 48:10891095.
114. Resetar, A., and, T. Spector. 1989. Glucuronidation of 3´-azido-3´-deoxythymidine: human and rat enzyme specificity. Biochem. Pharmacol. 38:13891393.
115. Sampath, J.,, M. Adachi,, S. Hatse,, L. Naesens,, J. Balzarini,, R. M. Flatley,, L. H. Matherly, and, J. D. Schuetz. 2002. Role of MRP4 and MRP5 in biology and chemotherapy. AAPS PharmSci. 4:19.
116. Sasiak, K., and, P. P. Saunders. 1996. Purification and properties of a human nicotinamide ribonucleoside kinase. Arch. Biochem. Biophys. 333:414418.
117. Sastry, J. K.,, P. N. Nehete,, S. Khan,, B. J. Nowak,, W. Plunkett,, R. B. Arlinghaus, and, D. Farquhar. 1992. Membrane-permeable dideoxyuridine 5´-monophosphate analogue inhibits human immunodeficiency virus infection. Mol. Pharmacol. 41:441445.
118. Sax, P. E.,, J. E. Gallant, and, P. E. Klotman. 2007. Renal safety of tenofovir disoproxil fumarate. AIDS Read. 17:90104.
119. Schneider, B.,, R. Sarfati,, D. Deville-Bonne, and, M. Veron. 2000. Role of nucleoside diphosphate kinase in the activation of anti-HIV nucleoside analogs. J. Bioenerg. Biomembr. 32:317324.
120. Schuetz, J. D.,, M. C. Connelly,, D. Sun,, S. G. Paibir,, P. M. Flynn,, R. V. Srinivas,, A. Kumar, and, A. Fridland. 1999. MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat. Med. 5:10481051.
121. Shaik, N.,, N. Giri,, G. Pan, and, W. F. Elmquist. 2007. Pglycoprotein-mediated active efflux of the anti-HIV 1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab. Dispos. 35:20762085.
122. Shaw, J. P.,, C. M. Sueoko,, R. Oliyai,, W. A. Lee,, M. N. Arimilli,, C. U. Kim, and, K. C. Cundy. 1997. Metabolism and pharmacokinetics of novel oral prodrugs of 9-[(R)-2-(phosphonomethoxy) propyl]adenine (PMPA) in dogs. Pharm. Res. 14:18241829.
123. Shewach, D. S.,, D. C. Liotta, and, R. F. Schinazi. 1993. Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2´-deoxycytidine kinase. Biochem. Pharmacol. 45:15401543.
124. Starrett, J. E., Jr.,, D. R. Tortolani,, M. J. Hitchcock,, J. C. Martin, and, M. M. Mansuri. 1992. Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine. Antivir. Res. 19:267273.
125. Streeter, D. G.,, J. T. Witkowski,, G. P. Khare,, R. W. Sidwell,, R. J. Bauer,, R. K. Robins, and, L. N. Simon. 1973. Mechanism of action of 1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc. Natl. Acad. Sci. USA 70:11741178.
126. Sugawara, M.,, W. Huang,, Y. J. Fei,, F. H. Leibach,, V. Ganapathy, and, M. E. Ganapathy. 2000. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 89:781789.
127. Takeda, M.,, S. Khamdang,, S. Narikawa,, H. Kimura,, Y. Kobayashi,, T. Yamamoto,, S. H. Cha,, T. Sekine, and, H. Endou. 2002. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J. Pharmacol. Exp. Ther. 300:918924.
128. Tong, L.,, T. K. Phan,, K. L. Robinson,, D. Babusis,, R. Strab,, S. Bhoopathy,, I. J. Hidalgo,, G. R. Rhodes, and, A. S. Ray. 2007. Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob. Agents Chemother. 51:34983504.
129. Traut, T. W. 1994. Physiological concentrations of purines and pyrimidines. Mol. Cell. Biochem. 140:122.
130. Uwai, Y.,, H. Ida,, Y. Tsuji,, T. Katsura, and, K. Inui. 2007. Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm. Res. 24:811815.
131. Vandercam, B.,, M. Moreau,, E. Goffin,, J. C. Marot,, J. P. Cosyns, and, M. Jadoul. 1999. Cidofovir-induced end-stage renal failure. Clin. Infect. Dis. 29:948949.
132. Van Rompay, A. R.,, M. Johansson, and, A. Karlsson. 2000. Phosphorylation of nucleosides and nucleoside analogs by mammalian nucleoside monophosphate kinases. Pharmacol. Ther. 87:189198.
133. Van Rompay, A. R.,, A. Norda,, K. Linden,, M. Johansson, and, A. Karlsson. 2001. Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases. Mol.Pharmacol. 59:11811186.
134. Veal, G. J.,, M. G. Barry,, S. H. Khoo, and, D. J. Back. 1997. In vitro screening of nucleoside analog combinations for potential use in anti-HIV therapy. AIDS Res. Hum. Retrovir. 13:481484.
135. Vere Hodge, R. A.,, D. Sutton,, M. R. Boyd,, M. R. Harnden, and, R. L. Jarvest. 1989. Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; penciclovir]. Anti-microb. Agents Chemother. 33:17651773.
136. Wainberg, M. A.,, P. Cahn,, R. C. Bethell,, J. Sawyer, and, S. Cox. 2007. Apricitabine: a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of nucleoside-resistant HIV infection. Antivir. Chem. Chemother. 18:6170.
137. Walsh, J. S.,, M. J. Reese, and, L. M. Thurmond. 2002. The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes. Chem. Biol. Interact. 142:135154.
138. Waters, L. J.,, G. Moyle,, S. Bonora,, A. D’Avolio,, L. Else,, S. Mandalia,, A. Pozniak,, M. Nelson,, B. Gazzard,, D. Back, and, M. Boffito. 2007. Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients. Antivir. Ther. 12:825830.
139. Weidner, D. A.,, E. G. Bridges,, E. M. Cretton, and, J. P. Sommadossi. 1992. Comparative effects of 3´-azido-3´-deoxythymidine and its metabolite 3´-amino-3´-deoxythymidine on hemoglobin synthesis in K-562 human leukemia cells. Mol. Pharmacol. 41:252258.
140. White, A. J. 2001. Mitochondrial toxicity and HIV therapy. Sex. Transm. Infect. 77:158173.
141. Whitley, R.,, C. Alford,, F. Hess, and, R. Buchanan. 1980. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs 20:267282.
142. Willis, R. C.,, D. A. Carson, and, J. E. Seegmiller. 1978. Adenosine kinase initiates the major route of ribavirin activation in a cultured human cell line. Proc. Natl. Acad. Sci. USA 75:30423044.
143. Wu, J. Z.,, G. Larson,, H. Walker,, J. H. Shim, and, Z. Hong. 2005. Phosphorylation of ribavirin and viramidine by adenosine kinase and cytosolic 5´-nucleotidase II: implications for ribavirin metabolism in erythrocytes. Antimicrob. Agents Chemother. 49:21642171.
144. Yao, S. Y.,, A. M. Ng,, M. Sundaram,, C. E. Cass,, S. A. Baldwin, and, J. D. Young. 2001. Transport of antiviral 3´-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol. Membr. Biol. 18:161167.
145. Zhu, C.,, M. Johansson,, J. Permert, and, A. Karlsson. 1998. Enhanced cytotoxicity of nucleoside analogs by overexpression of mitochondrial deoxyguanosine kinase in cancer cell lines. J. Biol. Chem. 273:1470714711.
146. Zimmermann, H. 1992. 5´-Nucleotidase: molecular structure and functional aspects. Biochem. J. 285:345365.

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