ZIDOVUDINE PHARMACOKINETICS IN ZIDOVUDINE-INDUCED BONE-MARROW TOXICITY

1 The major adverse effect of zidovudine (ZDV) is haematological toxic ity which results in anaemia and granulocytopenia. The aim of the pres ent study was to investigate if HIV-positive patients developing eryth roid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, ido -3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2 Twelve HIV-p ositive male patients were studied, six having developed bone marrow a plasia/hypoplasia within the first 6 months of ZDV therapy. Each of th e patients exhibiting toxicity were matched for age, weight, risk fact ors for HIV infection and disease stage with patients who had no evide nce of early bone marrow toxicity. 3 ZDV was administered orally in do ses 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 pharmacokinet ic parameters between the two groups of patients. For patients with ea rly 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 contr ol group. Similarly there was no significant difference in the pharmac okinetics of GZDV or the urinary ratio of GZDV to ZDV. 5 Therefore, de spite the fact that ZDV toxicity to haematopoietic progenitor cells ha s been previously shown to be dose related, there was no indication fr om this study that it is directly related to plasma concentrations of ZDV.