The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
HIV-1 Protease Inhibitors Are Substrates for the MDR 1 Multidrug Transporter
Abstract
The FDA approved HIV-1 protease inhibitors, ritonavir, saquinavir, and indinavir, are very effective in inhibiting HIV-1 replication, but their long-term efficacy is unknown. Since in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether these protease inhibitors are recognized by the MDR1 multidrug transporter (P-glycoprotein, or P-gp), thereby reducing their intracellular accumulation. In vitro studies in isolated membrane preparations from insect cells infected with MDR1-expressing recombinant baculovirus showed that these inhibitors significantly stimulated P-gp-specific ATPase activity and that this stimulation was inhibited by SDZ PSC 833, a potent inhibitor of P-gp. Furthermore, photoaffinity labeling of P-gp with the substrate analogue [125I]iodoarylazidoprazosin (IAAP) was inhibited by all three inhibitors. Cell-based approaches to evaluate the ability of these protease inhibitors to compete for transport of known P-gp substrates showed that all three HIV-1 protease inhibitors were capable of inhibiting the transport of some of the known P-gp substrates but their effects were generally weaker than other documented P-gp modulators such as verapamil or cyclosporin A. Inhibition of HIV-1 replication by all three protease inhibitors was reduced but could be restored by MDR1 inhibitors in cells expressing MDR1. These results indicate that the HIV-1 protease inhibitors are substrates of the human multidrug transporter, suggesting that cells in patients that express the MDR1 transporter will be relatively resistant to the anti-viral effects of the HIV-1 protease inhibitors, and that absorption, excretion, and distribution of these inhibitors in the body may be affected by the multidrug transporter.
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Cites
BIOCHEMISTRY OF MULTIDRUG RESISTANCE MEDIATED BY THE MULTIDRUG TRANSPORTER
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Self-citationGENETIC ANALYSIS OF THE MULTIDRUG TRANSPORTER
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Brain Microvascular and Astrocyte Localization of P‐Glycoprotein
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Cited by
Targeting multidrug resistance in cancer
Szakács, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1984 · Cited by 3,609
Self-citationDeeley, R. G., Westlake, C., & Cole, S. P. C. (2006) · Physiological Reviews · doi:10.1152/physrev.00035.2005 · Cited by 761
Effects of the Antifungal Agents on Oxidative Drug Metabolism: Clinical Relevance
Venkatakrishnan, K., von Moltke, L. L., & Greenblatt, D. J. (2000) · Clinical Pharmacokinetics · doi:10.2165/00003088-200038020-00002 · Cited by 508
Impact of Drug Transporter Studies on Drug Discovery and Development
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St John's Wort increases expression of P‐glycoprotein: Implications for drug interactions
Hennessy, M., Kelleher, D., Spiers, J. P., Barry, M., Kavanagh, P., Back, D., Mulcahy, F., & Feely, J. (2002) · British Journal of Clinical Pharmacology · doi:10.1046/j.0306-5251.2001.01516.x · Cited by 280
Metadata
- Authors
- Lee, C. G. L., Gottesman, M. M., Cardarelli, C. O., Ramachandra, M., Jeang, K.-T., Ambudkar, S. V., Pastan, I., & Dey, S.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-02-26
- Volume
- 37
- Issue
- 11
- Pages
- 3594-3601
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2003623971
- Cited by
- 477
- References
- 13
- FWCI
- 15.19
- Type
- journal article
- Language
- en
- Open access
- closed
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- Lee, C. G. L., Gottesman, M. M., Cardarelli, C. O., Ramachandra, M., Jeang, K.-T., Ambudkar, S. V., Pastan, I., & Dey, S. (1998). HIV-1 Protease Inhibitors Are Substrates for the MDR 1 Multidrug Transporter. Biochemistry. https://doi.org/10.1021/bi972709x
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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