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Antimicrob Agents Chemother. 1994 July; 38(7): 1541–1547.
PMCID: PMC284590

Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus.


As part of an effort towards optimization of dosing of zidovudine (ZDV), formation and elimination of total phosphorylated ZDV (ZDVPt) in peripheral blood mononuclear cells were examined in 21 asymptomatic human immunodeficiency virus-infected patients during their first 24 weeks of therapy (AIDS Clinical Trials Group Protocol 161). Intracellular concentrations of ZDVPt were measured with a previously described and validated radioimmunoassay technique. Although ZDV phosphorylation occurred readily upon initiation of therapy, it declined with time; the area under the concentration-time curve (AUC) at week 4 (mean +/- standard deviation, 3.41 +/- 0.93 pmol.h/10(6) cells) was significantly greater than that at week 24 (2.19 +/- 1.10 pmol.h/10(6) cells). Plasma ZDV AUC did not change with time and did not correlate with ZDVPt AUC. In dose-response experiments (20 to 100 mg orally), phosphorylation did not proportionally increase with increasing plasma ZDV concentrations. Similarly, compared with a single dose, two doses of ZDV over an 8-h period resulted in little ZDVPt increase in cells relative to increase in plasma ZDV concentrations. The half-life of intracellular ZDVPt was twice that of plasma ZDV (4 versus 2 h), suggesting that an every-8-h dosing regimen is justifiable. These findings suggest that metabolism of ZDV to its active intracellular forms may be saturable in some patients, is poorly correlated with plasma concentrations, and diminishes over time. These findings have implications for future development and management of anti-human immunodeficiency virus nucleoside therapy.

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Selected References

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  • Avramis VI, Kwock R, Solorzano MM, Gomperts E. Evidence of in vitro development of drug resistance to azidothymidine in T-lymphocytic leukemia cell lines (Jurkat E6-1/AZT-100) and in pediatric patients with HIV-1 infection. J Acquir Immune Defic Syndr. 1993 Dec;6(12):1287–1296. [PubMed]
  • Avramis VI, Markson W, Jackson RL, Gomperts E. Biochemical pharmacology of zidovudine in human T-lymphoblastoid cells (CEM). AIDS. 1989 Jul;3(7):417–422. [PubMed]
  • Bridges EG, Faraj A, Sommadossi JP. Inhibition of mammalian DNA polymerase-associated 3' to 5' exonuclease activity by 5'-monophosphates of 3'-azido-3'-deoxythymidine and 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1993 Apr 22;45(8):1571–1576. [PubMed]
  • Samuels ME, Koop CE, Hartsock PI. Single-use syringes. N Engl J Med. 1991 Apr 4;324(14):996–997. [PubMed]
  • Collins JM, Unadkat JD. Clinical pharmacokinetics of zidovudine. An overview of current data. Clin Pharmacokinet. 1989 Jul;17(1):1–9. [PubMed]
  • Fischl MA, Parker CB, Pettinelli C, Wulfsohn M, Hirsch MS, Collier AC, Antoniskis D, Ho M, Richman DD, Fuchs E, et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group. N Engl J Med. 1990 Oct 11;323(15):1009–1014. [PubMed]
  • Furman PA, Fyfe JA, St Clair MH, Weinhold K, Rideout JL, Freeman GA, Lehrman SN, Bolognesi DP, Broder S, Mitsuya H, et al. Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333–8337. [PubMed]
  • Harrington JA, Reardon JE, Spector T. 3'-azido-3'-deoxythymidine (AZT) monophosphate: an inhibitor of exonucleolytic repair of AZT-terminated DNA. Antimicrob Agents Chemother. 1993 Apr;37(4):918–920. [PMC free article] [PubMed]
  • Johnston MI, Hoth DF. Present status and future prospects for HIV therapies. Science. 1993 May 28;260(5112):1286–1293. [PubMed]
  • Kuster H, Vogt M, Joos B, Nadai V, Lüthy R. A method for the quantification of intracellular zidovudine nucleotides. J Infect Dis. 1991 Oct;164(4):773–776. [PubMed]
  • Laskin OL, de Miranda P, Blum MR. Azidothymidine steady-state pharmacokinetics in patients with AIDS and AIDS-related complex. J Infect Dis. 1989 Apr;159(4):745–747. [PubMed]
  • Liliemark J, Peterson C. Pharmacokinetic optimisation of anticancer therapy. Clin Pharmacokinet. 1991 Sep;21(3):213–231. [PubMed]
  • Lotterer E, Ruhnke M, Trautmann M, Beyer R, Bauer FE. Decreased and variable systemic availability of zidovudine in patients with AIDS if administered with a meal. Eur J Clin Pharmacol. 1991;40(3):305–308. [PubMed]
  • Morse GD, Shelton MJ, O'Donnell AM. Comparative pharmacokinetics of antiviral nucleoside analogues. Clin Pharmacokinet. 1993 Feb;24(2):101–123. [PubMed]
  • Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. [PubMed]
  • Robbins BL, Rodman J, McDonald C, Srinivas RV, Flynn PM, Fridland A. Enzymatic assay for measurement of zidovudine triphosphate in peripheral blood mononuclear cells. Antimicrob Agents Chemother. 1994 Jan;38(1):115–121. [PMC free article] [PubMed]
  • Slusher JT, Kuwahara SK, Hamzeh FM, Lewis LD, Kornhauser DM, Lietman PS. Intracellular zidovudine (ZDV) and ZDV phosphates as measured by a validated combined high-pressure liquid chromatography-radioimmunoassay procedure. Antimicrob Agents Chemother. 1992 Nov;36(11):2473–2477. [PMC free article] [PubMed]
  • Stretcher BN, Pesce AJ, Frame PT, Greenberg KA, Stein DS. Correlates of zidovudine phosphorylation with markers of HIV disease progression and drug toxicity. AIDS. 1994 Jun;8(6):763–769. [PubMed]
  • Stretcher BN, Pesce AJ, Hurtubise PE, Frame PT. Pharmacokinetics of zidovudine phosphorylation in patients infected with the human immunodeficiency virus. Ther Drug Monit. 1992 Aug;14(4):281–285. [PubMed]
  • Stretcher BN, Pesce AJ, Wermeling JR, Hurtubise PE. In vitro measurement of phosphorylated zidovudine in peripheral blood leucocytes. Ther Drug Monit. 1990 Sep;12(5):481–489. [PubMed]
  • Tartaglione TA, Collier AC, Coombs RW, Opheim KE, Cummings DK, Mackay SR, Benedetti J, Corey L. Acquired immunodeficiency syndrome. Cerebrospinal fluid findings in patients before and during long-term oral zidovudine therapy. Arch Neurol. 1991 Jul;48(7):695–699. [PubMed]
  • Törnevik Y, Jacobsson B, Britton S, Eriksson S. Intracellular metabolism of 3'-azidothymidine in isolated human peripheral blood mononuclear cells. AIDS Res Hum Retroviruses. 1991 Sep;7(9):751–759. [PubMed]

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