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Titolo:
Plasma drug levels compared with DNA incorporation of 3'-azido-3'-deoxythymidine (AZT) in adult cynomolgus (Macaca fascicularis) monkeys
Autore:
Olivero, OA; Reddy, MK; Pietras, SM; Poirier, MC;
Indirizzi:
NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA
Titolo Testata:
EXPERIMENTAL BIOLOGY AND MEDICINE
fascicolo: 5, volume: 226, anno: 2001,
pagine: 446 - 449
SICI:
1535-3702(200105)226:5<446:PDLCWD>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
VIRUS REVERSE-TRANSCRIPTASE; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; CELLULAR PHARMACOLOGY; ZIDOVUDINE; 3'-AZIDO-3'-DEOXYTHYMIDINE; CELLS; PHOSPHORYLATION; AZIDOTHYMIDINE; DAMAGE; MICE;
Keywords:
nucleoside analogs; zidovudine; cynomolgus; genotoxicity;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Olivero, OA NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, 37 Convent Dr,Bldg 37,Room 2A01, Bethesda, MD 20892 USA NCI 37 Convent Dr,Bldg 37,Room 2A01 Bethesda MD USA 20892 USA
Citazione:
O.A. 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

Abstract

Zidovudine (3 ' -azido-3 ' -deoxythymidine, AZT), widely used for the therapy of the Human Immunodeficiency Virus-1 (HIV-1), is a nucleoside analog of thymidine that becomes phosphorylated and incorporated into nuclear and mitochondrial DNA. Levels of AZT incorporation into DNA of humans, monkeys, and mice are highly variable and suggest interindividual variability in phosphorylation pathways. In addition, studies in rhesus monkeys (1) have shown a lack of correlation between levels of unbound AZT in plasma and tissue AZT-DNA. However, the correlation between plasma AZT and tissue AZT-DNA hasnot been previously examined in the same primate. Here we examine the relationship between AZT-DNA incorporation in leukocytes and multiple organs, and levels of the drug circulating in plasma of adult female cynomolgus (Macaca fascicularis) monkeys. Three monkeys were dosed with 40.0 mg of AZT/dayfor 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 (600mg/day) given to adult HIV-I-infected patients. In all three monkeys, at the time of sampling, values for AZT concentrations in plasma were similar and values for AZT incorporation into leukocyte DNA (86.1, 100.0, and 114.1 molecules of AZT/10(6) nucleotides) were also similar. AZT-DNA incorporation was defected in liver, uterus, spleen, and kidney from the three AZT-exposed animals, with values for positive samples ranging from 5.8 to 97.4 molecules of AZT/10(6) nucleotides, In brain cortex and lung DNA from AZT-exposed animals, AZT incorporation was undetectable. The data suggest that organ-specific differences in AZT uptake and/or metabolism may contribute to AZTphosphorylation and subsequent drug incorporation into DNA. In addition, AZT-DNA levels in monkey organs were similar to or lower than values observed in peripheral leukocytes of adult AIDS patients.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 22:19:53