Eagling V, Howe JL, Back DJ; International Conference on AIDS.
Int Conf AIDS. 1993 Jun 6-11; 9: 503 (abstract no. PO-B30-2205).
Department of Pharmacology and Therapeutics, University of Liverpool, England.
Toxicity to human haematopoietic progenitor cells resulting in anaemia and/or neutropenia in approximately 40% of patients is a major adverse effect associated with zidovudine (ZDV) administration. The mechanism of this toxicity remains unclear. Recently a minor metabolite of ZDV, 3'-amino-3'-deoxythymidine (AMT) was identified when human and rat liver microsomes and hepatocytes were incubated with ZDV and was found to be 5-7 times more toxic to human haematopoietic progenitor cells than ZDV (Cretton et al., 1991). We have investigated the formation of AMT by human liver microsomes, gastrointestinal bacteria and bone marrow. Formation of AMT by human liver microsomes was NADPH-dependent and enhanced approximately 3-fold by FAD and FMN. AMT formation was inhibited by ketoconazole (at concentrations less than 50 microM) and by carbon monoxide indicating involvement of a cytochrome P450 enzyme or cytochrome P450 reductase in its formation. AMT was formed by certain strains of gastrointestinal bacteria including Proteus Vulgaris and Clostridium Sporogenes, but was not formed in bone marrow aspirated from healthy volunteers and incubated with ZDV for upto 24 h. To date it has not been possible to quantify AMT in plasma using an hplc system validated for the assay of ZDV and its major, glucuronidated metabolite (GZDV) due to interference from endogenous compounds.
Publication Types:
Keywords:
- Animals
- Bone Marrow
- Cytochrome P-450 Enzyme System
- Hematopoietic Stem Cells
- Humans
- In Vitro
- Microsomes, Liver
- NADPH-Ferrihemoprotein Reductase
- Rats
- Zidovudine
Other ID:
UI: 102205208
From Meeting Abstracts