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. 1994 Jan;37(1):7–12. doi: 10.1111/j.1365-2125.1994.tb04231.x

Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity.

M Barry 1, J L Howe 1, D J Back 1, A M Swart 1, A M Breckenridge 1, I V Weller 1, N Beeching 1, F Nye 1
PMCID: PMC1364702  PMID: 8148221

Abstract

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.

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Selected References

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  1. Aboulker J. P., Swart A. M. Preliminary analysis of the Concorde trial. Concorde Coordinating Committee. Lancet. 1993 Apr 3;341(8849):889–890. doi: 10.1016/0140-6736(93)93096-j. [DOI] [PubMed] [Google Scholar]
  2. Agarwal R. P., Mian A. M. Thymidine and zidovudine metabolism in chronically zidovudine-exposed cells in vitro. Biochem Pharmacol. 1991 Jul 25;42(4):905–911. doi: 10.1016/0006-2952(91)90052-7. [DOI] [PubMed] [Google Scholar]
  3. Balis F. M., Pizzo P. A., Murphy R. F., Eddy J., Jarosinski P. F., Falloon J., Broder S., Poplack D. G. The pharmacokinetics of zidovudine administered by continuous infusion in children. Ann Intern Med. 1989 Feb 15;110(4):279–285. doi: 10.7326/0003-4819-110-4-279. [DOI] [PubMed] [Google Scholar]
  4. Barry M., Howe J., Back D., Breckenridge A., Brettle R., Mitchell R., Beeching N. J., Nye F. J. The effects of indomethacin and naproxen on zidovudine pharmacokinetics. Br J Clin Pharmacol. 1993 Jul;36(1):82–85. doi: 10.1111/j.1365-2125.1993.tb05898.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bhalla K., Birkhofer M., Li G. R., Grant S., MacLaughlin W., Cole J., Graham G., Volsky D. J. 2'-Deoxycytidine protects normal human bone marrow progenitor cells in vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with preservation of antiretroviral activity. Blood. 1989 Nov 1;74(6):1923–1928. [PubMed] [Google Scholar]
  6. Blum M. R., Liao S. H., Good S. S., de Miranda P. Pharmacokinetics and bioavailability of zidovudine in humans. Am J Med. 1988 Aug 29;85(2A):189–194. [PubMed] [Google Scholar]
  7. Child S., Montaner J., Tsoukas C., Fanning M., Le T., Wall R. A., Ruedy J. Canadian multicenter azidothymidine trial: AZT pharmacokinetics. J Acquir Immune Defic Syndr. 1991;4(9):865–870. [PubMed] [Google Scholar]
  8. Collier A. C., Bozzette S., Coombs R. W., Causey D. M., Schoenfeld D. A., Spector S. A., Pettinelli C. B., Davies G., Richman D. D., Leedom J. M. A pilot study of low-dose zidovudine in human immunodeficiency virus infection. N Engl J Med. 1990 Oct 11;323(15):1015–1021. doi: 10.1056/NEJM199010113231502. [DOI] [PubMed] [Google Scholar]
  9. Collins J. M., Unadkat J. D. Clinical pharmacokinetics of zidovudine. An overview of current data. Clin Pharmacokinet. 1989 Jul;17(1):1–9. doi: 10.2165/00003088-198917010-00001. [DOI] [PubMed] [Google Scholar]
  10. Cretton E. M., Xie M. Y., Bevan R. J., Goudgaon N. M., Schinazi R. F., Sommadossi J. P. Catabolism of 3'-azido-3'-deoxythymidine in hepatocytes and liver microsomes, with evidence of formation of 3'-amino-3'-deoxythymidine, a highly toxic catabolite for human bone marrow cells. Mol Pharmacol. 1991 Feb;39(2):258–266. [PubMed] [Google Scholar]
  11. Double blind dose-response study of zidovudine in AIDS and advanced HIV infection. Nordic Medical Research Councils' HIV Therapy Group. BMJ. 1992 Jan 4;304(6818):13–17. doi: 10.1136/bmj.304.6818.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Du D. L., Volpe D. A., Grieshaber C. K., Murphy M. J., Jr In vitro toxicity of 3'-azido-3'-deoxythymidine, carbovir and 2',3'-didehydro-2',3'-dideoxythymidine to human and murine haematopoietic progenitor cells. Br J Haematol. 1992 Apr;80(4):437–445. doi: 10.1111/j.1365-2141.1992.tb04555.x. [DOI] [PubMed] [Google Scholar]
  13. Fischl M. A., Parker C. B., Pettinelli C., Wulfsohn M., Hirsch M. S., Collier A. C., Antoniskis D., Ho M., Richman D. D., Fuchs E. 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. doi: 10.1056/NEJM199010113231501. [DOI] [PubMed] [Google Scholar]
  14. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy 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):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  15. Furman P. A., Fyfe J. A., St Clair M. H., Weinhold K., Rideout J. L., Freeman G. A., Lehrman S. N., Bolognesi D. P., Broder S., Mitsuya H. 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. doi: 10.1073/pnas.83.21.8333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gitterman S. R., Drusano G. L., Egorin M. J., Standiford H. C. Population pharmacokinetics of zidovudine. The Veterans Administration Cooperative Studies Group. Clin Pharmacol Ther. 1990 Aug;48(2):161–167. doi: 10.1038/clpt.1990.131. [DOI] [PubMed] [Google Scholar]
  17. Good S. S., Koble C. S., Crouch R., Johnson R. L., Rideout J. L., de Miranda P. Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans. Drug Metab Dispos. 1990 May-Jun;18(3):321–326. [PubMed] [Google Scholar]
  18. Herber R., Magdalou J., Haumont M., Bidault R., van Es H., Siest G. Glucuronidation of 3'-azido-3'-deoxythymidine in human liver microsomes: enzyme inhibition by drugs and steroid hormones. Biochim Biophys Acta. 1992 Jun 9;1139(1-2):20–24. doi: 10.1016/0925-4439(92)90077-z. [DOI] [PubMed] [Google Scholar]
  19. Izuta S., Saneyoshi M., Sakurai T., Suzuki M., Kojima K., Yoshida S. The 5'-triphosphates of 3'-azido-3'-deoxythymidine and 2', 3'-dideoxynucleosides inhibit DNA polymerase gamma by different mechanisms. Biochem Biophys Res Commun. 1991 Sep 16;179(2):776–783. doi: 10.1016/0006-291x(91)91884-f. [DOI] [PubMed] [Google Scholar]
  20. Klecker R. W., Jr, Collins J. M., Yarchoan R., Thomas R., Jenkins J. F., Broder S., Myers C. E. Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther. 1987 Apr;41(4):407–412. doi: 10.1038/clpt.1987.49. [DOI] [PubMed] [Google Scholar]
  21. Liu H. F., Vincent-Viry M., Galteau M. M., Guéguen R., Magdalou J., Nicolas A., Leroy P., Siest G. Urinary glucuronide excretion of fenofibric and clofibric acid glucuronides in man. Is it polymorphic? Eur J Clin Pharmacol. 1991;41(2):153–159. doi: 10.1007/BF00265909. [DOI] [PubMed] [Google Scholar]
  22. McDougal J. S., Martin L. S., Cort S. P., Mozen M., Heldebrant C. M., Evatt B. L. Thermal inactivation of the acquired immunodeficiency syndrome virus, human T lymphotropic virus-III/lymphadenopathy-associated virus, with special reference to antihemophilic factor. J Clin Invest. 1985 Aug;76(2):875–877. doi: 10.1172/JCI112045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miners J. O., Mackenzie P. I. Drug glucuronidation in humans. Pharmacol Ther. 1991;51(3):347–369. doi: 10.1016/0163-7258(91)90065-t. [DOI] [PubMed] [Google Scholar]
  24. Mitsuya H., Broder S. Strategies for antiviral therapy in AIDS. 1987 Feb 26-Mar 4Nature. 325(6107):773–778. doi: 10.1038/325773a0. [DOI] [PubMed] [Google Scholar]
  25. Morse G. D., Olson J., Portmore A., Taylor C., Plank C., Reichman R. C. Pharmacokinetics of orally administered zidovudine among patients with hemophilia and asymptomatic human immunodeficiency virus (HIV) infection. Antiviral Res. 1989 Mar;11(2):57–65. doi: 10.1016/0166-3542(89)90008-9. [DOI] [PubMed] [Google Scholar]
  26. Pluda J. M., Mitsuya H., Yarchoan R. Hematologic effects of AIDS therapies. Hematol Oncol Clin North Am. 1991 Apr;5(2):229–248. [PubMed] [Google Scholar]
  27. Pugh R. N., Murray-Lyon I. M., Dawson J. L., Pietroni M. C., Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646–649. doi: 10.1002/bjs.1800600817. [DOI] [PubMed] [Google Scholar]
  28. Rajaonarison J. F., Lacarelle B., De Sousa G., Catalin J., Rahmani R. In vitro glucuronidation of 3'-azido-3'-deoxythymidine by human liver. Role of UDP-glucuronosyltransferase 2 form. Drug Metab Dispos. 1991 Jul-Aug;19(4):809–815. [PubMed] [Google Scholar]
  29. Resetar A., Minick D., Spector T. Glucuronidation of 3'-azido-3'-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase. Significance of nucleoside hydrophobicity and inhibition by xenobiotics. Biochem Pharmacol. 1991 Jul 15;42(3):559–568. doi: 10.1016/0006-2952(91)90319-z. [DOI] [PubMed] [Google Scholar]
  30. Richman D. D., Fischl M. A., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Hirsch M. S. 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. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
  31. Sim S. M., Back D. J., Breckenridge A. M. The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes. Br J Clin Pharmacol. 1991 Jul;32(1):17–21. doi: 10.1111/j.1365-2125.1991.tb05607.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Simpson M. V., Chin C. D., Keilbaugh S. A., Lin T. S., Prusoff W. H. Studies on the inhibition of mitochondrial DNA replication by 3'-azido-3'-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem Pharmacol. 1989 Apr 1;38(7):1033–1036. doi: 10.1016/0006-2952(89)90245-1. [DOI] [PubMed] [Google Scholar]
  33. Singlas E., Pioger J. C., Taburet A. M., Colin J. N., Fillastre J. P. Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis. Clin Pharmacol Ther. 1989 Aug;46(2):190–197. doi: 10.1038/clpt.1989.125. [DOI] [PubMed] [Google Scholar]
  34. Sommadossi J. P., Carlisle R. Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro. Antimicrob Agents Chemother. 1987 Mar;31(3):452–454. doi: 10.1128/aac.31.3.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sommadossi J. P., Carlisle R., Zhou Z. Cellular pharmacology of 3'-azido-3'-deoxythymidine with evidence of incorporation into DNA of human bone marrow cells. Mol Pharmacol. 1989 Jul;36(1):9–14. [PubMed] [Google Scholar]
  36. Stagg M. P., Cretton E. M., Kidd L., Diasio R. B., Sommadossi J. P. Clinical pharmacokinetics of 3'-azido-3'-deoxythymidine (zidovudine) and catabolites with formation of a toxic catabolite, 3'-amino-3'-deoxythymidine. Clin Pharmacol Ther. 1992 Jun;51(6):668–676. doi: 10.1038/clpt.1992.79. [DOI] [PubMed] [Google Scholar]
  37. Stretcher B. N., Pesce A. J., Hurtubise P. E., Frame P. T. Pharmacokinetics of zidovudine phosphorylation in patients infected with the human immunodeficiency virus. Ther Drug Monit. 1992 Aug;14(4):281–285. doi: 10.1097/00007691-199208000-00004. [DOI] [PubMed] [Google Scholar]
  38. Stretcher B. N., Pesce A. J., Murray J. A., Hurtubise P. E., Vine W. H., Frame P. T. Concentrations of phosphorylated zidovudine (ZDV) in patient leukocytes do not correlate with ZDV dose or plasma concentrations. Ther Drug Monit. 1991 Jul;13(4):325–331. doi: 10.1097/00007691-199107000-00008. [DOI] [PubMed] [Google Scholar]
  39. Tartaglione T. A., Collier A. C., Opheim K., Gianola F. G., Benedetti J., Corey L. Pharmacokinetic evaluations of low- and high-dose zidovudine plus high-dose acyclovir in patients with symptomatic human immunodeficiency virus infection. Antimicrob Agents Chemother. 1991 Nov;35(11):2225–2231. doi: 10.1128/aac.35.11.2225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Temellini A., Giuliani L., Pacifici G. M. Interindividual variability in the glucuronidation and sulphation of ethinyloestradiol in human liver. Br J Clin Pharmacol. 1991 Jun;31(6):661–664. doi: 10.1111/j.1365-2125.1991.tb05589.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weidner D. A., Bridges E. G., Cretton E. M., Sommadossi J. P. 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. 1992 Feb;41(2):252–258. [PubMed] [Google Scholar]
  42. Yarchoan R., Klecker R. W., Weinhold K. J., Markham P. D., Lyerly H. K., Durack D. T., Gelmann E., Lehrman S. N., Blum R. M., Barry D. W. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986 Mar 15;1(8481):575–580. doi: 10.1016/s0140-6736(86)92808-4. [DOI] [PubMed] [Google Scholar]

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