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Cited by 477

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

Lee, Caroline G. L., Gottesman, Michael M., Cardarelli, Carol O., Ramachandra, Muralidhara, Jeang, Kuan-Teh, Ambudkar, Suresh V., Pastan, Ira, Dey, Saibal·1998·Biochemistry
DOI 10.1021/bi972709x
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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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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
DOI
10.1021/bi972709x
OpenAlex
W2003623971
Cited by
477
References
13
FWCI
15.19
Type
journal article
Language
en
Open access
closed

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