Oa. Olivero et al., Plasma drug levels compared with DNA incorporation of 3'-azido-3'-deoxythymidine (AZT) in adult cynomolgus (Macaca fascicularis) monkeys, EXP BIOL ME, 226(5), 2001, pp. 446-449
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.