The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors

Journal of Clinical Investigation

Volumn 101, Issue 2, 1998, Pages 289-294

  Kim, Richard B ^a   Fromm, Martin F ^a   Wandel, Christoph ^a   Leake, Brenda ^a   Wood, Alastair J J ^a   Roden, Dan M ^a   Wilkinson, Grant R ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AIDS; HIV 1 protease inhibitors; Membrane transport; P glycoprotein; Pharmacokinetics

Indexed keywords

GLYCOPROTEIN P; INDINAVIR; NELFINAVIR; PROTEINASE INHIBITOR; QUINIDINE; SAQUINAVIR; VALSPODAR;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CELL STRAIN CACO 2; CONTROLLED STUDY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BRAIN LEVEL; DRUG DISTRIBUTION; DRUG PENETRATION; DRUG TARGETING; DRUG TISSUE LEVEL; DRUG TRANSPORT; GENE DISRUPTION; HUMAN; HUMAN CELL; INTRAVENOUS DRUG ADMINISTRATION; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; PRIORITY JOURNAL;

EID: 0032518290     PISSN: 00219738     EISSN: None     Source Type: Journal    
DOI: 10.1172/JCI1269     Document Type: Article

References (26)

1. Carpenter, C.C.J., M.A. Fischl, S.M. Hammer, M.S. Hirsch, D.M. Jacobsen, D.A. Katzenstein, J.S. Montaner, D.D. Richman, M.S. Saag, R.T. Schooley, et al. 1996. Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. J. Am. Med. Assoc. 276:146-154.
2. Collier, A.C., R.W. Coombs, D.A. Schoenfeld, R.L. Bassett, J. Timpone, A. Baruch, M. Jones, K. Facey, C. Whitacre, V.J. McAuliffe, et al. 1996. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N. Engl. J. Med. 334:1011-1017.
3. Deeks, S.G., M. Smith, M. Holodniy, and J.O. Kahn. 1997. HIV-1 protease inhibitors. A review for clinicians. J. Am. Med. Assoc. 277:145-153.
4. Gottesman, M.M., and I. Pastan. 1993. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385-427.
5. Levêque, D., and F. Jehl. 1995. P-glycoprotein and pharmacokinetics. Anticancer Res. 15:331-336.
6. Cordon-Cardo, C., J.P. O'Brien, D. Casals, L. Rittman-Grauer, J.L. Biedler, M.R. Melamed, and J.R. Bertino. 1989. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA. 86:695-698.
7. Tsuji, A., T. Terasaki, Y. Takabatake, Y. Tenda, I. Tamai, T. Yamashima, S. Moritani, T. Tsuruo, and J. Yamashita. 1992. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 51:1427-1437.
8. Schinkel, A.H., J.J.M. Smit, O. van Tellingen, J.H. Beijnen, E. Wagenaar, L. van Deemter, C.A.A.M. Mol, M.A. van der Valk, E.C. Robanus-Maandag, H.P.J. Riele, et al. 1994. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 77:491-502.
9. Schinkel, A.H., E. Wagenaar, L. van Deemter, C.A.A.M. Mol, and P. Borst. 1995. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96:1698-1705.
10. Schinkel, A.H., E. Wagenaar, C.A.A.M. Mol, and L. van Deemter. 1996. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517-2524.
11. Bain, L.J., and G.A. LeBlanc. 1996. Interaction of structurally diverse pesticides with the human MDR1 gene product P-glycoprotein. Toxicol. Appl. Pharmacol. 141:288-298.
12. Ferry, D.R., H. Traunecker, and D.J. Kerr. 1996. Clinical trials of P-glycoprotein reversal in solid tumours. Eur. J. Cancer. 32A:1070-1081.
13. Ford, J.M. 1996. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur. J. Cancer. 32A: 991-1001.
14. Meunier, V., M. Bourrié, Y. Berger, and G. Fabre. 1995. The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications. Cell Biol. Toxicol. 11:187-194.
15. Kolars, J.C., P. Schmiedlin-Ren, J.D. Shuetz, C. Fang, and P.B. Watkins. 1992. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest. 90:1871-1878.
16. Sparreboom, A., J. van Asperen, U. Mayer, A.H. Schinkel, J.W. Smit, D.K. Meijer, P. Borst, W.J. Nooijen, J.H. Beijnen, and O. van Tellingen. 1997. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci. USA. 94:2031-2035.
17. Fojo, A.T., K. Ueda, D.J. Slamon, D.G. Poplack, M.M. Gottesman, and I. Pastan. 1987. Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. USA. 84:265-269.
18. Stein, D.S., D.G. Fish, J.A. Bilello, S.L. Preston, G.L. Martineau, and G.L. Drusano. 1996. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS. 10:485-492.
19. Rusconi, S., D.P. Merrill, and M.S. Hirsch. 1994. Inhibition of human immunodeficiency virus type 1 replication in cytokine-stimulated monocytes/ macrophages by combination therapy. J. Infect. Dis. 170:1361-1366.
20. Craig, J.C., I.B. Duncan, D. Hockley, C. Grief, N.A. Roberts, and J.S. Mills. 1991. Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antivir. Res. 16:295-305.
21. Bagasra, O., E. Lavi, L. Bobroski, K. Khalili, J.P. Pestaner, R. Tawadros, and R.J. Pomerantz. 1996. Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry. AIDS. 10:573-585.
22. Wiley, C.A., E. Masliah, and C.L. Achim. 1994. Measurement of CNS HIV burden and its association with neurologic damage. Adv. Neuroimmunol. 4:319-325.
23. Achim, C.L., R. Wang, D.K. Miners, and C.A. Wiley. 1994. Brain viral burden in HIV infection. J. Neuropathol. Exp. Neurol. 53:284-294.
24. Lucia, M.B., R. Cauda, A.L. Landay, W. Malorni, G. Donelli, and L. Ortona. 1995. Transmembrane P-glycoprotein (P-gp/P-170) in HIV infection: analysis of lymphocyte surface expression and drug-unrelated function. AIDS Res. Human Retroviruses. 11:893-901.
25. Didier, A.D., and F. Loor. 1995. Decreased biotolerability for ivermectin and cyclosporin A in mice exposed to potent P-glycoprotein inhibitors. Int. J. Cancer. 63:263-267.
26. Mayer, U., E. Wagenaar, B. Dorobek, J.H. Beijnen, P. Borst, and A.H. Schinkel. 1997. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier p-glycoprotein by oral treatment of mice with PSC833. J. Clin. Invest. 100:2430-2436.