Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3'-fluoro-3'- deoxythymidine and 3'-azido-3'-deoxythymidine Journal Article
| Authors: | Kong, X. B.; Zhu, Q. Y.; Vidal, P. M.; Watanabe, K. A.; Polsky, B.; Armstrong, D.; Ostrander, M.; Lang, S. A. Jr; Muchmore, E.; Chou, T. C. |
| Article Title: | Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3'-fluoro-3'- deoxythymidine and 3'-azido-3'-deoxythymidine |
| Abstract: | 3'-Fluoro-3'-deoxythymidine (FLT), a candidate anti-AIDS compound in clinical trials, showed anti-human immunodeficiency virus type 1 (HIV-1) potency (50% effective concentration, 0.0052 μM) slightly better than or equal to that of 3'-azido-3'-deoxythymidine (AZT) in MT4 cells and was threefold more potent in H9 cells. There was no FLT resistance demonstrable in the AZT-resistant HIV-1 strains. Both FLT and AZT showed low cytotoxicity for MT4 cells, with selectivity indices (efficacy/toxicity ratio) of >47,000 and >33,000, respectively. Cellular permeation of FLT and thymidine (dThd) was greater than that of AZT, and FLT and dThd permeated the cell membranes by a carrier-mediated mechanism as well as by simple diffusion, as indicated by the existence of nitrobenzylthioinosine-5'-monophosphate-sensitive and - insensitive components. By contrast, transport of AZT into cells was by simple diffusion. The intracellular level of the triphosphate of FLT (FLTTP) in MT4 cells was two- to threefold higher than that of AZT (AZTTP) after exposure to 1.8 μM each compound for 12 h. The elimination kinetics of FLTTP and AZTTP in HIV-1-infected MT4 cells in fresh medium showed biphasic patterns, with initial half-lives of 1.03 and 1.09 h, respectively. In phytohemagglutinin-stimulated human peripheral blood lymphocytes, the FLTTP level was increased 59-fold compared with that in unstimulated cells at 12 h, was four- to sixfold higher than the level of AZTTP in stimulated cells at 12 h, and remained four- to fivefold higher during a 4-h elimination period in fresh medium and twofold higher at the end of a 12-h elimination period. Two- to eightfold more [3H]AZT than [3H]FLT was incorporated into the host cell DNA, and both [3H]AZT and [3H]FLT remained persistently incorporated for over 24 h. The incorporated [3H]AZT and [3H]FLT were alkali labile, whereas incorporated [3H]dThd was alkali stable. Pharmacokinetics of FLT in plasma of monkeys after intravenous (i.v.) administration showed that the FLT concentration in plasma declined, with a half-life of 1.19 ± 0.1 h; the steady-state volume of distribution was 0.93 ± 0.2 liter/kg of body weight, and total clearance was 0.56 ± 0.15 liter/kg. Oral bioavailability of FLT was excellent and comparable to i.v. bioavailability in terms of areas under the concentration-time curves for three monkeys. Of the total dose, 41 to 61% was excreted in urine as unchanged FLT, and only 3.2 to 7.4% of the total dose was identified as glucuronide-conjugated FLT in urine 48 h after i.v. administration to monkeys. We conclude that FLT exhibits an anti-HIV-1 potency similar to that of AZT but with slightly better selectivity of effects and with higher intracellular active metabolite levels. |
| Keywords: | human cell; nonhuman; animal cell; cytotoxicity; drug potency; dna; acquired immune deficiency syndrome; drug bioavailability; drug metabolism; virus replication; drug half life; monkey; drug transport; drug diffusion; intravenous drug administration; antiviral activity; oral drug administration; zidovudine; cell membrane transport; cell membrane permeability; nucleotide; drug elimination; 3' fluorothymidine; urinary excretion; glucuronide; human; male; female; priority journal; article; nitrobenzylthioinosine |
| Journal Title: | Antimicrobial Agents and Chemotherapy |
| Volume: | 36 |
| Issue: | 4 |
| ISSN: | 0066-4804 |
| Publisher: | American Society for Microbiology |
| Date Published: | 1992-04-01 |
| Start Page: | 808 |
| End Page: | 818 |
| Language: | English |
| DOI: | 10.1128/aac.36.4.808 |
| PUBMED: | 1503443 |
| PROVIDER: | scopus |
| PMCID: | PMC189428 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 30 July 2019 -- Source: Scopus |
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