Zidovudine phosphorylation in HIV-infected patients and seronegative volunteers

Barry, Michael; Wild, Martin K.; Veal, Gareth J.; Back, David; Breckenridge, Alasdair; Fox, Raymond; Beeching, Nicholas; Nye, Fredrick; Carey, Peter; Timmins, Derek

doi:10.1097/00002030-199408000-00002

Cited by 61 publications

(39 citation statements)

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“…The phosphorylation of NRTIs occurs within cells, and therefore, cellular factors such as cellular kinases and efflux transporters may be critical determinants of the intracellular pharmacokinetics (23). In an analysis of nine study participants, we observed individual variability in the activities of cellular kinases, consistent with the findings of earlier studies (8,40,45). We also observed variability in the phosphorylation of different thymidine analogs (AZT and 4Ј-Ed4T) in some individuals.…”

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confidence: 87%

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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confidence: 87%

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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“…Overall, the intracellular pharmacokinetics for HIV-positive Thai patients were comparable to those described previously for Caucasians (1,(10)(11)(12). Higher intracellular levels of ZDVMP in HIV-positive Thais than in seronegative Thai subjects are in agreement with the results of similar studies with Caucasians.…”

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confidence: 88%

“…As the effect of ZDV is dependent on the rate and extent of intracellular activation, concentrations in plasma are of limited value in predicting efficacy or toxicity (1, 10). Intracellular phosphorylation studies performed with human immunodeficiency virus (HIV)-infected patients and healthy volunteers have been performed mostly with Caucasian patients (1,7,(10)(11)(12).…”

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confidence: 99%

“…PBMCs (5 ϫ 10 6 cells) were extracted with 60% methanol prior to separation of ZDV and its phosphate metabolites by high-performance liquid chromatography, as described previously (1). In brief, samples were eluted on a Partisil 10-SAX anion-exchange column (4.6 by 250 mm) using a mobile phase of ammonium dihydrogen phosphate buffer-methanol run as a gradient over 40 min.…”

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Pharmacokinetics of Zidovudine Phosphorylation in Human Immunodeficiency Virus-Positive Thai Patients and Healthy Volunteers

Wattanagoon

Bangchang

Hoggard

et al. 2000

Antimicrob Agents Chemother

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We assessed the pharmacokinetics of zidovudine (ZDV) in plasma and intracellular ZDV phosphate anabolites in peripheral blood mononuclear cells in Thai human immunodeficiency virus (HIV) type 1-infected patients and healthy volunteers. The plasma ZDV area under the concentration-time curve from 0 to 6 h (AUC 0-6 ) was similar in patients and healthy volunteers (32.77 and 22.77 mol/liter ⅐ h, respectively; confidence interval, ؊3.37 to 19.92). Although the concentration of ZDV triphosphate (ZDVTP) was similar in the two groups, the ZDV monophosphate (ZDVMP) AUC 0-6 was significantly greater in HIV patients (1.12 pmol/10 6 cells) than in healthy volunteers (0.15 pmol/10 6 cells). In agreement with previously published data obtained with Caucasians, the significant difference in intracellular phosphorylation in Thai volunteers and HIV patients is primarily due to ZDVMP. Comparing the data from this study with the data obtained with Caucasians suggests no marked ethnic differences in ZDV phosphorylation.Zidovudine (ZDV) is sequentially phosphorylated by host intracellular enzymes to its active form, ZDV triphosphate (ZDVTP) (4). ZDVTP competes with endogenous dTTP for incorporation into viral DNA, thus inhibiting viral DNA synthesis. Following incorporation of ZDVTP, the azido (N 3 ) group results in chain termination (9). As the effect of ZDV is dependent on the rate and extent of intracellular activation, concentrations in plasma are of limited value in predicting efficacy or toxicity (1, 10). Intracellular phosphorylation studies performed with human immunodeficiency virus (HIV)-infected patients and healthy volunteers have been performed mostly with Caucasian patients (1,7,(10)(11)(12).ZDV has a major role in resource-poor countries in the prevention of vertical transmission of HIV. A recent report from Thailand showed that ZDV administered orally during late pregnancy and delivery reduced HIV transmission from infected mothers to infants by 50% compared with a placebo group (16). However, no studies to date have investigated the metabolism of ZDV in an Asian population. There are known ethnic differences in drug metabolism (6, 17), and thus any differences in expression of enzymes involved in ZDV metabolism (glucuronyltransferase, CYP 3A, or, more importantly, cellular kinases [14]) would alter plasma and intracellular pharmacokinetics. In this study, we have examined ZDV pharmacokinetics with ZDV-naive, HIV-infected Thai patients and healthy volunteers.Twenty antiretroviral drug-naive HIV-positive patients, 3 females and 17 males, aged 21 to 54 years (median age, 26 years), and 7 male volunteers, aged 24 to 30 years (median age, 28 years), participated in this study. The patients had a median body weight of 53 kg (range, 42.5 to 73.0 kg). HIV-positive patients were at different disease stages (A1, n ϭ 2; A2, n ϭ 4; B1, n ϭ 1; B2, n ϭ 4; B3, n ϭ 5; and C3, n ϭ 4) (Centers for Disease Control and Prevention 1993 classification system), but all were stable at the time of sampling. Median CD4 cell counts were 246 ...

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“…The phosphorylation of ZDV in 12 HIV seropositive patients and 5 HIV seronegative volunteers has been investigated in our laboratory [26]. Each subject was given ZDV 250 mg orally and blood was taken at 1, 2, 4 and 6 h. Plasma and peripheral blood mononuclear cells (PBMC) were obtained at each time point and individual intracellular ZDV phosphate metabolites as well as plasma ZDV concentrations were measured.…”

Section: Pharmacokinetics and Clinical Practicementioning

confidence: 99%

Science, medicine and clinical pharmacology. The Lilly Lecture 1994.

Breckenridge

1995

Brit J Clinical Pharma

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Zidovudine phosphorylation in HIV-infected patients and seronegative volunteers

Cited by 61 publications

References 0 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

Pharmacokinetics of Zidovudine Phosphorylation in Human Immunodeficiency Virus-Positive Thai Patients and Healthy Volunteers

Science, medicine and clinical pharmacology. The Lilly Lecture 1994.

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