Plasma drug levels compared with DNA incorporation of 3'-azido-3'-deoxythymidine (AZT) in adult cynomolgus (Macaca fascicularis) monkeys

Zidovudine (3 ' -azido-3 ' -deoxythymidine, AZT), widely used for the thera py of the Human Immunodeficiency Virus-1 (HIV-1), is a nucleoside analog of thymidine that becomes phosphorylated and incorporated into nuclear and mi tochondrial DNA. Levels of AZT incorporation into DNA of humans, monkeys, a nd mice are highly variable and suggest interindividual variability in phos phorylation pathways. In addition, studies in rhesus monkeys (1) have shown a lack of correlation between levels of unbound AZT in plasma and tissue A ZT-DNA. However, the correlation between plasma AZT and tissue AZT-DNA has not been previously examined in the same primate. Here we examine the relat ionship between AZT-DNA incorporation in leukocytes and multiple organs, an d levels of the drug circulating in plasma of adult female cynomolgus (Maca ca fascicularis) monkeys. Three monkeys were dosed with 40.0 mg of AZT/day for 30 days by naso-gastric intubation. The average daily dose of 9.9 mg of AZT/kg/body wt was similar to the similar to8.6 mg of AZT/kg/body wt (600 mg/day) given to adult HIV-I-infected patients. In all three monkeys, at th e time of sampling, values for AZT concentrations in plasma were similar an d values for AZT incorporation into leukocyte DNA (86.1, 100.0, and 114.1 m olecules of AZT/10(6) nucleotides) were also similar. AZT-DNA incorporation was defected in liver, uterus, spleen, and kidney from the three AZT-expos ed animals, with values for positive samples ranging from 5.8 to 97.4 molec ules of AZT/10(6) nucleotides, In brain cortex and lung DNA from AZT-expose d animals, AZT incorporation was undetectable. The data suggest that organ- specific differences in AZT uptake and/or metabolism may contribute to AZT phosphorylation and subsequent drug incorporation into DNA. In addition, AZ T-DNA levels in monkey organs were similar to or lower than values observed in peripheral leukocytes of adult AIDS patients.