The motivation for the present clinical pharmacologic studies comes from recent observations on 3'-azido-3'-deoxythymidine (AZT) metabolism in our laboratory which demonstrated a novel pathway of AZT metabolism leading to the formation of 3'-amino-3'-deoxythymidine (AMT) and its 5'-omicron- glucuronide (GAMT). The quantitative importance of this AMT metabolite assessed in pilot studies both in rhesus monkeys and patients, combined with the evidence of its high toxicity for human bone marrow cells, demonstrate the crucial need to re-evaluate the metabolism of AZT given orally in AIDS patients. Analytical methodologies with high sensitivity, selectivity, and reproducibility will be developed to quantitate AMT and GAMT in biological fluids of AIDS patients. Using these assays, the linearity of AZT drug metabolism toward AMT formation will be assessed by comparison of AMT levels after administration of low doses versus high doses of AZT. The time required to reach and maintain steady-state concentrations of AMT at current standard doses and dosing interval of AZT (500 mg/day), as well as the potential of induced AMT formation by chronic AZT administration will be assessed. Potential pharmacogenetic variations in AZT conversion to AMT will be determined by evaluating this metabolism in different populations of HIV-infected patients (Caucasians, blacks, hispanics). Hepatic metabolic drug-drug interaction of AZT metabolism with P450 inducers and inhibitors of glucuronidation will be determined to assess whether AMT formation is enhanced under these conditions. The potential relationship between AZT and AMT pharmacokinetic parameters determined in the different studied populations and protocols with markers of toxic events will also be evaluated. These clinical pharmacologic studies will be done in conjunction with molecular pharmacologic studies which will provide insights into the mechanism(s) responsible for AZT- induced anemia via inhibition by AZT and metabolites (with emphasis on AMT) of genes that regulate hemoglobin synthesis. Following evidence of decreased intracellular hemoglobin levels in reticulocytes of patients treated with AZT, expression of genes that regulate both globin and heme pathways (including 5-aminolevulinate synthase, 5-aminolevulinate dehydrase, and phosphobilinogen deaminase) will be determined and compared to constitutively expressed genes. The influence of hemin to reverse inhibition of """"""""hemoglobin genes"""""""" by AZT and/or metabolites will be examined. It is hoped that these comprehensive clinical and molecular pharmacologic studies will provide insight into dosing regimens and observed individual variations in AZT toxicity and efficacy, as well as with elucidation of mechanism(s) involved in the toxic effects of this anti-AIDS drug observed in patients, either used as a single agent or in combination chemotherapy.
Showing the most recent 10 out of 71 publications
