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Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice

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Abstract

P-glycoprotein inhibitors can increase the oral bioavailability of paclitaxel. We have now explored the mechanisms that determine the efficacy of several novel P-glycoprotein inhibitors to increase the absorption of paclitaxel from the gut lumen of mice in both in vivo and in vitro experiments. The inhibitors studied were cyclosporin A, PSC 833, GF120918, LY335979 and R101933. Mass balance studies showed that GF120918 was the most effective inhibitor, resulting in almost complete uptake of paclitaxel. PSC 833 was slightly less effective, whereas cyclosporin A and LY335979 were moderately effective. R101933 had only marginal effects. These findings were in line with in vitro transport experiments using LLC-mdr1a cells. By studying the intra-intestinal kinetics of the agents we found that cyclosporin A, PSC 833 and GF120918 rapidly passed the stomach and traveled concurrently with paclitaxel through the intestines, whereas LY335979 and R101933 delayed stomach emptying. Moreover, these latter compounds appear to be more readily absorbed when released into the intestines thus reducing local intestinal concentrations. Due to their combined effects on absorption and metabolic elimination of paclitaxel, cyclosporin A and PSC 833 resulted in the highest paclitaxel levels in plasma. In conclusion, our models provide insight into the factors that determine the suitability of P-glycoprotein inhibitors to enable oral paclitaxel therapy and will be useful in selecting candidate inhibitors for clinical testing.

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References

  1. Biedler JL, Riehm H: Cellular resistance to actinomycin D in Chinese hamster cells in vitro: Cross-resistance, radioautographic, and cytogenetic studies. Cancer Res 30: 1174–1184, 1970

    CAS  PubMed  Google Scholar 

  2. Juliano RL, Ling V: A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455: 152–162, 1976

    CAS  PubMed  Google Scholar 

  3. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I: Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84: 265–269, 1987

    CAS  PubMed  Google Scholar 

  4. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC: Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84: 7735–7738, 1987

    CAS  PubMed  Google Scholar 

  5. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86: 695–698, 1989

    CAS  PubMed  Google Scholar 

  6. Schinkel AH, Smit JJM, Van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CAAM, van der Valk MA, Robanus-Maandag EC, te Riele HPJ, Berns AJM, Borst P: 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, 1994

    Article  CAS  PubMed  Google Scholar 

  7. Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DKF, Borst P, Nooijen WJ, Beijnen JH, Van Tellingen O: 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, 1997

    Article  CAS  PubMed  Google Scholar 

  8. Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, Miyake K, Resau JH, Bates SE: The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci 113: 2011–2021, 2000

    CAS  PubMed  Google Scholar 

  9. Kruijtzer CMF, Boot H, Beijnen JH, Lochs HL, Parnis FX, Planting AST, Pelgrims JMG, Williams R, Mathot RAA, Rosing H, Schot ME, Van Tinteren H, Schellens JHM: Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer. Ann Oncol 14: 197–204, 2003

    Article  CAS  PubMed  Google Scholar 

  10. Meerum Terwogt JM, Malingre MM, Beijnen JH, ten Bokkel Huinink WW, Rosing H, Koopman FJ, Van Tellingen O, Swart M, Schellens JHM: Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5: 3379–3384, 1999

    CAS  PubMed  Google Scholar 

  11. Malingre MM, Terwogt JM, Beijnen JH, Rosing H, Koopman FJ, Van Tellingen O, Duchin K, Huinink WW, Swart M, Lieverst J, Schellens JHM: Phase I and pharmacokinetic study of oral paclitaxel. J Clin Oncol 18: 2468–2475, 2000

    CAS  PubMed  Google Scholar 

  12. van Asperen J, Van Tellingen O, Sparreboom A, Schinkel AH, Borst P, Nooijen WJ, Beijnen JH: Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer 76: 1181–1183, 1997

    PubMed  Google Scholar 

  13. van Asperen J, Van Tellingen O, van der Valk MA, Rozenhart M, Beijnen JH: Enhanced oral absorption and decreased elimination of paclitaxel in mice with cyclosporin A. Clin Cancer Res 4: 2293–2297, 1998

    CAS  PubMed  Google Scholar 

  14. Britten CD, Baker SD, Denis LJ, Johnson T, Drengler R, Siu LL, Duchin K, Kuhn J, Rowinsky EK: Oral paclitaxel and concurrent cyclosporin A: Targeting clinically relevant systemic exposure to paclitaxel. Clin Cancer Res 6: 3459–3468, 2000

    CAS  PubMed  Google Scholar 

  15. Bardelmeijer HA, Beijnen JH, Brouwer KR, Rosing H, Nooijen WJ, Schellens JHM, Van Tellingen O: Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin Cancer Res 6: 4416–4421, 2000

    CAS  PubMed  Google Scholar 

  16. Boesch D, Gaveriaux C, Jachez B, Pourtier-Manzanedo A, Bollinger P, Loor F: In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res 51: 4226–4233, 1991

    CAS  PubMed  Google Scholar 

  17. Hyafil F, Vergely C, Du Vignaud P, Grand-Perret T: In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res 53: 4595–4602, 1993

    CAS  PubMed  Google Scholar 

  18. Dantzig AH, Shepard RL, Cao J, Law KL, Ehlhardt WJ, Baughman TM, Bumol TF, Starling JJ: Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res 56: 4171–4179, 1996

    CAS  PubMed  Google Scholar 

  19. van Zuylen L, Sparreboom A, van der Gaast A, van der Burg ME, van Beurden V, Bol CJ, Woestenborghs R, Palmer PA, Verweij J: The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel. Clin Cancer Res 6: 1365–1371, 2000

    CAS  PubMed  Google Scholar 

  20. Schinkel AH, Mayer U, Wagenaar E, Mol CAAM, van Deemter L, Smit JJM, van der Valk MA, Voordouw AC, Spits H, Van Tellingen O, Zijlmans JM, Fibbe WE, Borst P: Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94: 4028–4033, 1997

    Article  CAS  PubMed  Google Scholar 

  21. Schinkel AH, Wagenaar E, van Deemter L, Mol CAAM, Borst P: 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, 1995

    CAS  PubMed  Google Scholar 

  22. Sparreboom A, Van Tellingen O, Nooijen WJ, Beijnen JH: Determination of paclitaxel and metabolites in mouse plasma, tissues, urine and faeces by semi-automated reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Appl 664: 383–391, 1995

    Article  CAS  PubMed  Google Scholar 

  23. Van Tellingen O, Kemper M, Tijssen F, van Asperen J, Nooijen WJ, Beijnen JH: High-performance liquid chromatographic bioanalysis of PSC 833 in human and murine plasma. J Chromatogr B Biomed Sci Appl 719: 251–257, 1998

    CAS  PubMed  Google Scholar 

  24. Bardelmeijer HA, Ouwehand M, Beijnen JH, Schellens JHM, Van Tellingen O: Determination of cyclosporin A in human and mouse plasma by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 763: 201–206, 2001

    CAS  PubMed  Google Scholar 

  25. Kemper EM, Jansen B, Brouwer KR, Schellens JHM, Beijnen JH, Van Tellingen O: Bioanalysis and preliminary pharmacokinetics of the acridone carboxamide derivative GF120918 in plasma of mice and humans by ion-pairing reversed-phase high-performance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl 759: 135–143, 2001

    CAS  PubMed  Google Scholar 

  26. Thomas H, Coley HM: Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10: 159–165, 2003

    PubMed  Google Scholar 

  27. Lehnert M, Degiuli R, Kunke K, Emerson S, Dalton WS, Salmon SE: Serum can inhibit reversal of multidrug resistance by chemosensitisers. Eur J Cancer 32A: 862–867, 1996

    CAS  PubMed  Google Scholar 

  28. Ludescher C, Eisterer W, Hilbe W, Hofmann J, Thaler J: Decreased potency of MDR-modulators under serum conditions determined by a functional assay. Br J Haematol 91: 652–657, 1995

    CAS  PubMed  Google Scholar 

  29. Cresteil T, Monsarrat B, Alvinerie P, Treluyer JM, Vieira I, Wright M: Taxol metabolism by human liver microsomes: Identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 54: 386–392, 1994

    CAS  PubMed  Google Scholar 

  30. Thummel KE, Wilkinson GR: In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38: 389–430, 1998

    CAS  PubMed  Google Scholar 

  31. Fischer V, Rodriguezgascon A, Heitz F, Tynes R, Hauck C, Cohen D, Vickers AEM: The multidrug resistance modulator valspodar (PSC833) is metabolized by human cytochrome P450 3A—Implications for drug-drug interactions and pharmacological activity of the main metabolite. Drug Metab Dispos 26: 802–811, 1998

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Heleen A. Bardelmeijer, Mariët Ouwehand, Jos H. Beijnen, Jan H. M. Schellens & Olaf van Tellingen

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  1. Heleen A. Bardelmeijer
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  2. Mariët Ouwehand
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  3. Jos H. Beijnen
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  4. Jan H. M. Schellens
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  5. Olaf van Tellingen
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Bardelmeijer, H.A., Ouwehand, M., Beijnen, J.H. et al. Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice. Invest New Drugs 22, 219–229 (2004). https://doi.org/10.1023/B:DRUG.0000026248.45084.21

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  • DOI: https://doi.org/10.1023/B:DRUG.0000026248.45084.21

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