Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2‘,3‘-dideoxynucleoside analogs in resting and activated human cells.

Gao, Wen Yi; Agbaria, Riad; Driscoll, John S.; Mitsuya, Hiroaki

doi:10.1016/s0021-9258(18)99923-0

Cited by 209 publications

(26 citation statements)

References 25 publications

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“…One possible explanation is that thymidine analogue zidovudine is preferentially phosphorylated in activated cells as the level of thymidine kinase (involved in the initial monophosphorylation step) is cell-cycle regulated, its activity being higher in activated cells than in quiescent cells. By contrast, lamivudine and tenofovir are cell cycle activation-independent agents, which are effective in both quiescent and activated cells; lamivudine being preferentially phosphorylated in activated cells and tenofovir in quiescent cells [63][64][65][66].…”

Section: Nucleoside/nucleotide Reverse Transcriptase Inhibitorsmentioning

confidence: 99%

Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Male and Female Genital Tract

et al. 2011

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HIV resides within anatomical 'sanctuary sites', where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Suboptimal antiretroviral concentrations in the genital tract may result in compartmentalized viral replication, selection of resistant mutations and possible re-entry of wild-type/resistant virus into the systemic circulation. Therefore, achieving adequate antiretroviral exposure in the genital tract has implications for the prevention of sexual and vertical transmission of HIV. Penetration of antiretrovirals in the genital tract is expressed by accumulation ratios derived from the measurement of drug concentrations in time-matched seminal plasma/cervicovaginal fluid and plasma samples. Penetration varies by gender and may be drug (as opposed to class) specific with high interindividual variability. Concentrations in seminal plasma are highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of newer agents, raltegravir and maraviroc, is moderate (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide). In the female genital tract, the nucleoside analogues exhibit high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists between individuals and study centres. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, demonstrate effective accumulation in cervicovaginal secretions (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir).

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Section: Nucleoside/nucleotide Reverse Transcriptase Inhibitorsmentioning

confidence: 99%

Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Male and Female Genital Tract

et al. 2011

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“…In addition to a dependence on the concentration of the parent drug, it is now recognized that triphosphate formation is dependent also on the activation state of the target cell. 11,12 Thus, relationships between systemic concentrations of the parent drug and the intracellular triphosphate are complex and multifactorial. This provides an explanation for why there will be greater variability in concentrations at the site of action than in systemic circulation.…”

Section: Pharmacokinetic Variabilitymentioning

confidence: 99%

Pharmacologic Considerations for Therapeutic Success with Antiretroviral Agents

Fletcher

1999

Ann Pharmacother

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Treatment of the individual who is infected with HIV is a challenging long-term undertaking. Optimal management requires synthesis of a rapidly evolving base of basic and clinical knowledge. The selection of an antiretroviral regimen based on an understanding of the degree to which each individual agent possesses the desired pharmacologic characteristics should help the healthcare provider to translate the therapeutic principles of treatment of HIV infection into clinical reality for all patients.

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“…Older women demonstrated positive associations of these cytokines with FTCtp concentrations, as hypothesized. Cellular activation state, which we did not measure here, contributes to the phosphorylation rate in vitro, with TDF undergoing metabolism equally well in active and resting cells and lamivudine undergoing metabolism preferentially in resting cells (34,35). Given the structural similarity between lamivudine and FTC (36), this phenomenon is generally extrapolated to FTC; potential differences in cellular activation between young and old women may partially explain our observations.…”

Section: Discussionmentioning

confidence: 85%

Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine

Dumond

Bay

Nelson³

et al. 2020

Antimicrob Agents Chemother

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The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IM; tenofovir diphosphate [TFVdp], FTCtp) to their endogenous nucleotides (EN; dATP and dCTP, respectively), a potential treatment efficacy marker, was assessed among participants of the Women's Interagency HIV Study (WIHS), who ranged from 25-75 years. Samples from women receiving TDF/FTC with viral load <200 copies/mL were dichotomized by age at collection into two groups (≤45 years, ≥60 years). IM/EN concentrations were measured in peripheral blood mononuclear cell (PBMC) pellets; IL-6 and sCD163 were measured in plasma; senescent CD8+ T cells were measured in viable PBMCs. The TFVdp:dATP and FTCtp:dCTP ratios had statistically significantly different distributions in older and younger women (log-rank test p=0.0023 and p=0.032, respectively); in general, IM and EN concentrations were higher in the older women. After adjusting for potential confounders, these findings were not significant. In women ≤45 years, TFVdp was negatively associated with IL-6 and sCD163, while FTCtp was positively associated with sCD163 and IL-6 in women ≥60 years. BMI was positively associated with IL-6 in both age groups, and negatively associated with TFVdp in women ≤45 years. After adjustment, age remained significant for sCD163, while Black race, BMI, and renal function remained significant for several IMs and ENs, suggesting that factors associated with aging, but not age itself, govern intracellular TDF/FTC pharmacology.

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Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2‘,3‘-dideoxynucleoside analogs in resting and activated human cells.

Cited by 209 publications

References 25 publications

Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Male and Female Genital Tract

Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Male and Female Genital Tract

Pharmacologic Considerations for Therapeutic Success with Antiretroviral Agents

Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine

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