Journal Article

The Cellular Pharmacology of Nucleoside- and Nucleotide-Analogue Reverse-Transcriptase Inhibitors and Its Relationship to Clinical Toxicities

Peter L. Anderson, Thomas N. Kakuda and Kenneth A. Lichtenstein

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 38, issue 5, pages 743-753
Published in print March 2004 | ISSN: 1058-4838
Published online March 2004 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/381678
The Cellular Pharmacology of Nucleoside- and Nucleotide-Analogue Reverse-Transcriptase Inhibitors and Its Relationship to Clinical Toxicities

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Nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors (NRTIs) require intracellular phosphorylation for anti–human immunodeficiency virus (HIV) activity and toxicity. Long-term toxicities associated with NRTIs may be related to overactivation of this process. In vitro experiments have shown increased rates of NRTI and endogenous nucleoside phosphorylation to be associated with cellular activation. Patients with advanced HIV disease often have overexpression of cytokines, which corresponds to an elevated cellular activation state. These patients also have higher rates of NRTI phosphorylation and NRTI toxicity, suggesting an interaction between a proinflammatory biological state, NRTI phosphorylation, and toxicity. Studies suggest that women may have higher rates of NRTI phosphorylation than do men, as well as increased risk for NRTI-induced toxicity. Future research is needed to understand the NRTI activation process and improve the long-term toxicity profile of NRTIs. Such research should include comparisons of NRTI phosphorylation according to sex and cellular activation state (i.e., elevated vs. low).

Journal Article.  7390 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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