Pharmaceutical Research

, Volume 16, Issue 8, pp 1206–1212

Role of P-Glycoprotein on the CNS Disposition of Amprenavir (141W94), an HIV Protease Inhibitor

  • Joseph W. Polli
  • Jeanne L. Jarrett
  • Scott D. Studenberg
  • Joan E. Humphreys
  • Steven W. Dennis
  • Kenneth R. Brouwer
  • Joseph L. Woolley
Article

Abstract

Purpose. To determine the role of P-glycoprotein (Pgp) on the CNS penetration of the HIV protease inhibitor (PI) amprenavir (141W94) and to test the hypothesis that co-administration of a second HIV PI (ritonavir) could enhance amprenavir's brain penetration in vivo.

Methods. Pgp-mediated efflux was investigated in vitro with Caco-2 cells and in vivo by whole-body autoradiography (WBA). 'Genetic'mdrla/lbdouble knockout mice, 'chemical' Pgp knockout mice generated by administration of the Pgp inhibitor GF120918, and mice pretreated with ritonavir were used in WBA studies to investigate the effects of Pgp modulation on the CNS penetration of amprenavir.

Results. Amprenavir, indinavir, ritonavir, and saquinavir had 2-to 23-fold higher transport rates from the basolateral to apical direction than from the apical to basolateral direction across Caco-2 monolayers. Incubation with GF 120918 negated this difference, suggesting that the efflux was Pgp-mediated. WBA studies demonstrated a 13- and 27-fold increase in the brain and a 3.3-fold increase in the CSF concentrations of amprenavir in mice pretreated with GF120918 and in mdrla/lbdouble knockout mice. In contrast, pretreatment with ritonavir did not alter the CNS exposure of amprenavir.

Conclusions. These results provide evidence that amprenavir and other HIV PIs are Pgp substrates and that co-administration of a specific Pgp inhibitor will enhance amprenavir's CNS penetration in vivo. These results will have an important therapeutic impact in the treatment of AIDS dementia.

ritonavir whole-body autoradiography blood-brain barrier cytochrome P450 Caco-2 

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REFERENCES

  1. 1.
    J. Adkins and D Faulds. Amprenavir. Drugs 55:837-842 (1998).Google Scholar
  2. 2.
    A. Carr and D. Cooper. HIV Protease Inhibitors. AIDS 10:S151-S157 (1996).Google Scholar
  3. 3.
    J. Lewis. Protease Inhibitors: A therapeutic breakthrough for the treatment of patients with human immunodeficiency virus. Clin. Ther. 19:187-214 (1997).Google Scholar
  4. 4.
    P. Portegies. Review of antiretroviral therapy in the prevention of HIV-related AIDS Dementia Complex (ADC). Drugs 49:25-31 (1995).Google Scholar
  5. 5.
    H. Gendelman, Y. Persidski, A. Ghorpade, J. Limoges, M. Stins, M. Fiala, and R. Morrisett. The neuropathogenesis of the AIDS dementia complex. AIDS 11:S35-S45 (1997).Google Scholar
  6. 6.
    P. Preiss. P-glycoprotein and related transporters. Int. J. Clin. Pharmarcol. Ther. 36:3-8 (1998).Google Scholar
  7. 7.
    S. Letrent, G. Pollack, K. R. Brouwer, and K. L. R Brouwer. Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat. Pharm. Res. 15:599-605 (1998).Google Scholar
  8. 8.
    G. Luker, V. Rao, C. Crankshaw, J. Dahlheimer, and D. Piwnica-Worms. Characterization of phosphine complexes of technetium (III) as transport substrates of the multidrug resistance P-glycoprotein and functional markers of P-glycoprotein at the blood-brain barrier. Biochemistry 36:14218-14227 (1997).Google Scholar
  9. 9.
    J. Polli, J. Humphreys, S. Good, S. Studenberg, H. Robertson White, J. Jarrett, and C. Serabjit-Singh. Validation of an in vitro blood brain barrier model: A case study examining the CNS penetration of anti-HIV compounds in vitro and in vivo. Pharm Res. 14:674 (1997).Google Scholar
  10. 10.
    R. Kim, M. Fromm, C. Wandel, B. Leake, A. Wood, D. Roden, and G. Wilkinson. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101:289-294 (1998).Google Scholar
  11. 11.
    C. Lee, M. Gottesman, C. Cardarelli, M. Ramachandra, K.-T. Jeang, S. Ambudkar, I. Pastan, and S. Dey. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 37:3594-3601 (1998).Google Scholar
  12. 12.
    C. Washington, G. Duran, B. Sikic, and T. Blaschke. Saquinavir is a high affinity substrate for the multidrug transporter, P-glycoprotein. Clin. Pharmacol. Ther. 61:193 (1997).Google Scholar
  13. 13.
    J. Alsenz, H. Steffen, and R Alex. Active apical secretory efflux of HIV protease inhibitors saquinavir and ritonavir in Caco-2 cell monolayers. Pharm Res. 15:423-428 (1998).Google Scholar
  14. 14.
    L. Gan, S. Yanni, and D. Thakker. Modulation of tight junctions of the Caco-2 cell monolayer by H2-antagonists. Pharm. Res. 15:53-57 (1998).Google Scholar
  15. 15.
    K. Hosoya, K.-J. Kim, and V. Lee. Age-dependent expression of P-glycoprotein gp170 in Caco-2 cell monolayers. Pharm. Res. 13:885-890 (1996).Google Scholar
  16. 16.
    S. Studenberg, R. Dahl, G. Bowers, I. Correa, S. Castellino, D. Chapman, B. Whitby, P. Zavorskas, and J. Woolley. The Disposition of [14C]-Amprenavir in Rats. PharmSci Supp. 1:S673 (1998).Google Scholar
  17. 17.
    H. Schinkel, U. Mayer, E. Wagenaar, C. Mol, L. van Deemter, J. Smit, M. van der Valk, A. Voordouw, H. Spits, O. van Tellingre, J. Mark, J. Zijlmans, W. Fibbe, and P. Borst. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug transporting) P-glycoproteins. Proc. Natl. Acad. Sci. USA 94:4028-4033 (1997).Google Scholar
  18. 18.
    F. Hyafil, C. Vergely, P. Du Vignaud, and T. Grand-Perret. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxaminde derivative. Cancer Res. 53:4595-4602 (1993).Google Scholar
  19. 19.
    U. Germann, P. Ford, D. Shlyakhter, V. Mason, and M. Harding. Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209, and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein, MRP. Anticancer Drugs 8:141-155 (1997).Google Scholar
  20. 20.
    J. Kempf, K. Marsh, G. Kimar, A. Rodrigues, J. Denissen, E. McDonald, M. Kukulka, A. Hsu, G. Granneman, P. Baroldi, et. al., Leonard. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob. Agents Chemother. 41:654-660 (1997).Google Scholar
  21. 21.
    J. Jarrett, S. Studenberg, H. Robertson White, and J. Woolley. Quantitative whole-body autoradiography study of the HIV protease inhibitor 141W94 after a single oral dose of [14C]-141W94 to rats. ISSX Proceedings 12:108 (1997).Google Scholar
  22. 22.
    D. Livingston, S. Pazhanisamy, D. Porter, and G. Painter. Weak binding of VX-478 to human plasma proteins and implications for anti-human immunodeficiency virus therapy. J. Infect. Dis. 172:1238-1245 (1995).Google Scholar
  23. 23.
    A. Gooding, A. Hsieh, and J. Woolley. Plasma protein binding and erythrocyte partitioning studies in rats, dogs, and humans with the HIV-1 protease inhibitor, 141W94 (VX-478). ISSX Proceedings 10:347 (1996).Google Scholar
  24. 24.
    A. Mosley, K. Brouwer, and K. R. Brouwer. In Vitro Evaluation of the Serum Binding of an Acridone Carboximide Derivative (GW918), a Potent Inhibitor of P-Glycoprotein. American Association of the Colleges of Pharmacy. Pharm. Res. 13:5-420 (1996).Google Scholar
  25. 25.
    C. Cordon-Cardo, J. O'Brien, D. Casals, L. Rittman-Grauer, J. Biedler, M. Melamed, and J. Bertino. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at the blood-brain barrier site. Proc. Natl. Acad. Sci. USA 86:695-698 (1989).Google Scholar
  26. 26.
    Y. Zhang, X. Guo, E. Lin, and L. Benet. Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for novel cysteine protease inhibitors. Drug. Metab. Dispos. 26:360-366 (1998).Google Scholar
  27. 27.
    V. Wacher, C. Wu, and L. Benet. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinog. 13:129-134 (1995).Google Scholar
  28. 28.
    L. Jette, E. Beaulieu, J.-M. Leclerc, and R. Beliveau. Cyclosporin A treatment induces overexpression of P-glycoprotein in kidney and other tissues. Am. J. Physiol. 270:F756-F765 (1996).Google Scholar
  29. 29.
    S. Glynn and M. Yazdanian. In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. J. Pharm. Sci. 87:306-310 (1998).Google Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Joseph W. Polli
    • 1
  • Jeanne L. Jarrett
    • 1
  • Scott D. Studenberg
    • 1
  • Joan E. Humphreys
    • 1
  • Steven W. Dennis
    • 2
  • Kenneth R. Brouwer
    • 1
  • Joseph L. Woolley
    • 1
  1. 1.Division of Bioanalysis and Drug MetabolismGlaxo Wellcome, Inc.Research Triangle Park
  2. 2.BioScience SupportGlaxo Wellcome, Inc.Research Triangle Park

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