Comparison of the Phosphorylation of 4′-Ethynyl 2′,3′-Dihydro-3′-Deoxythymidine with That of Other Anti-Human Immunodeficiency Virus Thymidine Analogs

Hsu, Chih‐Hung; Hu, Rong; Dutschman, Ginger E.; Yang, Guangwei; Krishnan, Preethi; Tanaka, Hiromichi; Baba, Masanori; Cheng, Yung‐Chi

doi:10.1128/aac.01432-06

Cited by 15 publications

(23 citation statements)

References 36 publications

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“…We also observed variability in the phosphorylation of different thymidine analogs (AZT and 4Ј-Ed4T) in some individuals. This may be due to the fact that the substrate specificity of the kinases at each phosphorylation step may be different or that more than one enzyme may be responsible for phosphorylation at each step (24,39). Turriziani et al also observed individual variability in TK-1 activity, though the variability was more marked in HIV-infected individuals than in healthy individuals (45).…”

Section: Downloaded Frommentioning

confidence: 90%

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Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Paintsil¹,

Dutschman²,

Hu³

et al. 2011

Antimicrob Agents Chemother

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Individual variation in response to antiretroviral therapy is well-known, but it is not clear if demographic characteristics such as gender, age, and ethnicity are responsible for the variation. To optimize anti-HIV therapy and guide antiretroviral drug discovery, determinants that cause variable responses to therapy need to be evaluated. We investigated the determinants of intracellular concentrations of nucleoside analogs using peripheral blood mononuclear cells from 40 healthy donors. We observed individual differences in the concentrations of the intracellular nucleoside analogs; the mean concentrations of the triphosphate metabolite of ethynylstavudine (4-Ed4T), zidovudine (AZT), and lamivudine (3TC) were 0.71 pmol/10 6 cells (minimum and maximum, 0.10 and 3.00 pmol/10 6 cells, respectively), 0.88 pmol/10 6 cells (minimum and maximum, 0.10 and 15.18 pmol/10 6 cells, respectively), and 1.70 pmol/10 6 cells (minimum and maximum, 0.20 and 7.73 pmol/10 6 cells, respectively). Gender and ethnicity had no effect on the concentration of 4-Ed4T and 3TC metabolites. There was a trend for moderation of the concentrations of AZT metabolites by gender (P ‫؍‬ 0.17 for gender ⅐ metabolite concentration). We observed variability in the activity and expression of cellular kinases. There was no statistically significant correlation between thymidine kinase 1 (TK-1) activity or expression and thymidine analog metabolite concentrations. The correlation between the activity of deoxycytidine kinase (dCK) and the 3TC monophosphate metabolite concentration showed a trend toward significance (P ‫؍‬ 0.1). We observed an inverse correlation between the multidrug-resistant protein 2 (MRP2) expression index and the concentrations of AZT monophosphate, AZT triphosphate, and total AZT metabolites. Our findings suggest that the observed variation in clinical response to nucleoside analogs may be due partly to the individual differences in the intracellular concentrations, which in turn may be affected by the cellular kinases involved in the phosphorylation pathway and ATP-binding cassette (ABC) transport proteins.Individual variation in response, such as viral suppression and adverse effects, to antiretroviral therapy is a well-described phenomenon (19, 49). Epidemiological and limited clinical studies suggest that demographic characteristics (e.g., gender, age, and ethnicity) and the HIV disease state of an individual may be partly responsible for the variation in efficacy and toxicity observed with treatment by nucleoside analog reverse transcriptase inhibitors (NRTIs). For example, published studies show that women experienced a 4-fold lower rate of disease progression than did men while they were on zidovudine (AZT) monotherapy; however, women experienced exaggerated toxicities during NRTI therapy compared to those of men (15-17, 20, 37). Gender and ethnicity have been suggested to be possible variables that explain the observed differences in treatment response to NRTIs (1,16,43).In a cohort of 4 HIV-1-infected women and 29 HIV-1-in...

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Section: Downloaded Frommentioning

confidence: 90%

“…Phopshoglyceral kinase (PGK) can phosphorylate the diphosphate metabolites of nucleoside analogs such as AZT and ethynlystavudine (4Ј-Ed4T), a novel inhibitor, to their triphosphate metabolites (24). NRTI triphosphate is incorporated into HIV DNA by HIV reverse transcriptase (RT) and causes termination of HIV DNA chain elongation (27).…”

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confidence: 99%

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Paintsil¹,

Dutschman²,

Hu³

et al. 2011

Antimicrob Agents Chemother

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“…Stepwise phosphorylation of festinavir occurs via the same enzymes as stavudine. Thymidine kinase 1 phosphorylates festinavir to festinavir-MP with 4-fold greater efficiency than stavudine (Hsu et al, 2007). The efficiency of festinavir-MP phosphorylation by thymidinylate monophosphate kinase is approximately 10 % of that seen for stavudine-MP or zidovudine-MP.…”

Section: Festinavirmentioning

confidence: 71%

“…The efficiency of festinavir-MP phosphorylation by thymidinylate monophosphate kinase is approximately 10 % of that seen for stavudine-MP or zidovudine-MP. Conversion from festinavir-DP to festinavir-TP appears to be catalyzed by multiple enzymes including nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, and 3-phosphoglycerate kinase (Hsu et al, 2007). In contrast to other thymidine analogs which are readily catabolized by thymidine phosphorylase, festinavir catabolism cannot be detected.…”

Section: Festinavirmentioning

confidence: 90%

Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors

Herman¹,

Sluis‐Cremer²

2012

Pharmacology

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“…65 Nucleoside diphosphate kinase and 3'phosphoglycerate kinase converts ZDV-DP to the triphosphate form and 3'phosphoglycerate kinase converts 3TC-DP to the triphosphate form. 66 The main dephosphorylation enzymes are 5'nucleotidases, which oppose the first phosphorylation step and convert monophosphates back to the parent drug. 67 Phosphotases are broad-spectrum dephosphorylation enzymes that can also dephosphorylate drug-phosphates to the parent drug.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

Zidovudine and Lamivudine for HIV Infection

Anderson

Rower²

2010

Clinical Medicine Reviews in Therapeutics

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Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

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Comparison of the Phosphorylation of 4′-Ethynyl 2′,3′-Dihydro-3′-Deoxythymidine with That of Other Anti-Human Immunodeficiency Virus Thymidine Analogs

Cited by 15 publications

References 36 publications

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors

Zidovudine and Lamivudine for HIV Infection

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