The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities.
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).
Anderson
Peter L
PL
University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. peter.anderson@uchsc.edu
Kakuda
Thomas N
TN
Lichtenstein
Kenneth A
KA
D000998:Antiviral Agents / Q000494:pharmacology; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009705:Nucleosides / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D000998:Antiviral Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase