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An Examination of the Effect of Intestinal First Pass Extraction on Intestinal Lymphatic Transport of Saquinavir in the Rat

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Abstract

Purpose

To assess the impact of intestinally based efflux/elimination processes on the extent of intestinal lymphatic transport of saquinavir. To compare the relative effects of co-administration of P-gp/CYP modulators on intestinal lymphatic transport versus systemic bioavailability of saquinavir.

Methods

A cremophor mixed micelle formulation of saquinavir alone, or co-administered with P-gp/CYP modulators, verapamil, ketoconazole or cyclosporine, was dosed intraduodenally in the mesenteric lymph duct cannulated anaesthetized rat model.

Results

Co-administration of P-gp/CYP modulators resulted in significant increases in the extent of intestinal lymphatic transport of saquinavir. A comparison of the relative enhancement of lymphatic transport and plasma bioavailability compared to control (i.e. saquinavir alone) reveals a greater effect of verapamil and ketoconazole on the amount of drug transported by the lymphatic route, an observation consistent with a preferential targeting of saquinavir via the intestinal lymphatics. In contrast co-administration of cyclosporine increased both the extent of lymphatic transport (5.5-fold), and systemic bioavailability (4.1-fold).

Conclusions

Intestinal P-gp/CYP efflux/elimination restricts saquinavir transport via the intestinal lymphatics in the rat. Targeted increases in intestinal lymphatic levels of saquinavir may be achieved by selective inhibition of intestinal P-gp and/or CYP.

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Abbreviations

CYP:

Cytochrome P450

P-gp:

P glycoprotein

SQV:

Saquinavir

TG:

Triglyceride

References

  1. C. M. Perry and S. Noble. Saquinavir soft-gel capsule formulation. A review of its use in patients with HIV infection. Drugs 55:461–486 (1998).

    Article  PubMed  CAS  Google Scholar 

  2. S. M. Hammer, M. S. Saag, M. Schechter, J. S. G. Montaner, R. T. Schooley, D. M. Jacobsen, M. A. Thompson, C. C. J. Carpenter, M. A. Fischl, B. G. Gazzard, J. M. Gatell, M. S. Hirsch, D. A. Katzenstein, D. D. Richman, S. Vella, P. G. Yeni, and P. A. Volberding. Treatment for adult HIV infection—2006 recommendations of the International AIDS Society—USA panel. JAMA 296:827–843 (2006).

    Article  PubMed  CAS  Google Scholar 

  3. M. E. Fitzsimmons and J. M. Collins. Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. Drug Metab. Dispos. 25:256–266 (1997).

    PubMed  CAS  Google Scholar 

  4. M. Frohlich, M. M. Hoffmann, J. Burhenne, G. Mikus, J. Weiss, and W. E. Haefeli. Association of the CYP3A5 A6986G (CYP3A5*3) polymorphism with saquinavir pharmacokinetics. Br. J. Clin. Pharmacol. 58:443–444 (2004).

    Article  PubMed  Google Scholar 

  5. J. Alsenz, H. Steffen, and R. Alex. Active apical secretory efflux of the HIV protease inhibitors saquinavir and ritonavir in Caco-2 cell monolayers. Pharm. Res. 15:423–428 (1998).

    Article  PubMed  CAS  Google Scholar 

  6. C. B. Washington, H. R. Wiltshire, M. Man, T. Moy, S. R. Harris, E. Worth, P. Weigl, Z. Liang, D. Hall, L. Marriott, and T. F. Blaschke. The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells. Drug Metab. Dispos. 28:1058–1062 (2000).

    PubMed  CAS  Google Scholar 

  7. V. J. Wacher, C. Y. Wu, and L. Z. 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).

    Article  PubMed  CAS  Google Scholar 

  8. K. E. Thummel, K. L. Kunze, and D. D. Shen. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv. Drug Deliv. Rev. 27:99–127 (1997).

    Article  PubMed  CAS  Google Scholar 

  9. P. J. Sinko, J. R. Kunta, H. H. Usansky, and B. A. Perry. Differentiation of gut and hepatic first pass metabolism and secretion of saquinavir in ported rabbits. J. Pharmacol. Exp. Ther. 310:359–366 (2004).

    Article  PubMed  CAS  Google Scholar 

  10. S. J. Mouly, M. F. Paine, and P. B. Watkins. Contributions of CYP3A4, P-glycoprotein, and serum protein binding to the intestinal first-pass extraction of saquinavir. J. Pharmacol. Exp. Ther. 308:941–948 (2004).

    Article  PubMed  CAS  Google Scholar 

  11. G. Pantaleo, C. Graziosi, and A. S. Fauci. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N. Engl. J. Med. 328:327–335 (1993).

    Article  PubMed  CAS  Google Scholar 

  12. H. F. Gunthard, D. V. Havlir, S. Fiscus, Z. Q. Zhang, J. Eron, J. Mellors, R. Gulick, S. D. Frost, A. J. Brown, W. Schleif, F. Valentine, L. Jonas, A. Meibohm, C. C. Ignacio, R. Isaacs, R. Gamagami, E. Emini, A. Haase, D. D. Richman, and J. K. Wong. Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J. Infect. Dis. 183:1318–1327 (2001).

    Article  PubMed  CAS  Google Scholar 

  13. O. J. Cohen and A. S. Fauci. Current strategies in the treatment of HIV infection. DM Disease-a-Month 48:150–184 (2002).

    Google Scholar 

  14. M. Guadalupe, S. Sankaran, M. D. George, E. Reay, D. Verhoeven, B. L. Shacklett, J. Flamm, J. Wegelin, T. Prindiville, and S. Dandekar. Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection. J. Virol. 80:8236–8247 (2006).

    Article  PubMed  CAS  Google Scholar 

  15. C. O’Driscoll. Intestinal lymphatic targeting of drugs. STP Pharma Sciences 13:17–25 (2003).

    CAS  Google Scholar 

  16. B. T. Griffin and C. M. O’Driscoll. A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model. J. Pharm. Pharmacol. 58:917–925 (2006).

    Article  PubMed  CAS  Google Scholar 

  17. C. A. Cuvelier, F. Berlioz, S. C. Dautrey, C. Roze, C. Carbon, and R. Farinotti. Intestinal absorption of saquinavir in the rat: insights in possible mechanisms. Gastroenterology 114:A957 (1998).

    Article  Google Scholar 

  18. C. Flexner. Dual protease inhibitor therapy in HIV-infected patients: pharmacologic rationale and clinical benefits. Annu. Rev. Pharmacol. Toxicol. 40:649–674 (2000).

    Article  PubMed  CAS  Google Scholar 

  19. H. Saitoh and B. J. Aungst. Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine. Pharm. Res. 12:1304–1310 (1995).

    Article  PubMed  CAS  Google Scholar 

  20. M. Maurice, L. Pichard, M. Daujat, I. Fabre, H. Joyeux, J. Domergue, and P. Maurel. Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture. FASEB J. 6:752–758 (1992).

    PubMed  CAS  Google Scholar 

  21. M. A. Gibbs, M. T. Baillie, D. D. Shen, K. L. Kunze, and K. E. Thummel. Persistent inhibition of CYP3A4 by ketoconazole in modified Caco-2 cells. Pharm. Res. 17:299–305 (2000).

    Article  PubMed  CAS  Google Scholar 

  22. M. J. Siegsmund, C. Cardarelli, I. Aksentijevich, Y. Sugimoto, I. Pastan, and M. M. Gottesman. Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells. J. Urol. 151:485–491 (1994).

    PubMed  CAS  Google Scholar 

  23. R. B. Kim, C. Wandel, B. Leake, M. Cvetkovic, M. F. Fromm, P. J. Dempsey, M. M. Roden, F. Belas, A. K. Chaudhary, D. M. Roden, A. J. Wood, and G. R. Wilkinson. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm. Res. 16:408–414 (1999).

    Article  PubMed  CAS  Google Scholar 

  24. M. Naito and T. Tsuruo. Competitive inhibition by verapamil of ATP-dependent high affinity vincristine binding to the plasma membrane of multidrug-resistant K562 cells without calcium ion involvement. Cancer Res. 49:1452–1455 (1989).

    PubMed  CAS  Google Scholar 

  25. R. D. Whalen, P. N. V. Tata, G. J. Burckart, and R. Venkataramanan. Species differences in the hepatic and intestinal metabolism of cyclosporine. Xenobiotica 29:3–9 (1999).

    Article  PubMed  CAS  Google Scholar 

  26. L. Salphati and L. Z. Benet. Effects of ketoconazole on digoxin absorption and disposition in rat. Pharmacology 56:308–313 (1998).

    Article  PubMed  CAS  Google Scholar 

  27. R. Sandström, T. W. Knutson, L. Knutson, B. Jansson, and H. Lennernäs. The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans. Br. J. Clin. Pharmacol. 48:180–189 (1999).

    Article  PubMed  Google Scholar 

  28. C. M. O’ Driscoll, R. A. Myers, and V. J. Stella. Blood and lymph transport of DDT after oral and parenteral administration to anaesthetized rats. Int. J. Pharm. 73:177–183 (1991).

    Article  CAS  Google Scholar 

  29. W. E. Hamlin, J. I. Northam, and J. G. Wagner. Relationship between in vitro dissolution rates and solubilities of numerous compounds representative of various chemical species. J. Pharm. Sci. 54:1651–1653 (1965).

    Article  CAS  Google Scholar 

  30. L. Sek, B. J. Boyd, W. N. Charman, and C. J. H. Porter. Examination of the impact of a range of pluronic surfactants on the in-vitro solubilisation behaviour and oral bioavailability of lipiclic formulations of atovaquone. J. Pharm. Pharmacol. 58:809–820 (2006).

    Article  PubMed  CAS  Google Scholar 

  31. J. F. Cuine, W. N. Charman, C. W. Pouton, G. A. Edwards, and C. J. H. Porter. Increasing the proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in beagle dogs. Pharm. Res. 24:748–757 (2007).

    Article  PubMed  CAS  Google Scholar 

  32. W. N. A. Charman, and V. J. Stella. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34:175–178 (1986).

    Article  CAS  Google Scholar 

  33. M. Achira, H. Suzuki, K. Ito, and Y. Sugiyama. Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P450 3A4. AAPS PharmSci 1 (1999).

  34. F. Seeballuck, M. B. Ashford, and C. M. O’Driscoll. The effects of Pluronic (R) block copolymers and Cremophor (R) EL on intestinal lipoprotein processing and the potential link with P-glycoprotein in Caco-2 cells. Pharm. Res. 20:1085–1092 (2003).

    Article  PubMed  CAS  Google Scholar 

  35. K. Brinkman, F. Huysmans, and D. M. Burger. Pharmacokinetic interaction between saquinavir and cyclosporine. Ann. Intern. Med. 129:914–915 (1998).

    PubMed  CAS  Google Scholar 

  36. S. Noble and D. Faulds. Saquinavir—A review of its pharmacology and clinical potential in the management of HIV infection. Drugs 52:93–112 (1996).

    Article  PubMed  CAS  Google Scholar 

  37. C. M. O’Driscoll. Lipid-based formulations for intestinal lymphatic delivery. Eur. J. Pharm. Sci. 15:405–415 (2002).

    Article  PubMed  CAS  Google Scholar 

  38. N. L. Trevaskis, C. J. H. Porter, and W. N. Charman. The lymph lipid precursor pool is a key determinant of intestinal lymphatic drug transport. J. Pharmacol. Exp. Ther. 316:881–891 (2006).

    Article  PubMed  CAS  Google Scholar 

  39. S. M. Khoo, J. H. Porter, G. A. Edwards, and W. N. Charman. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole. J. Pharm. Sci. 87:1538–1541 (1998).

    Article  PubMed  CAS  Google Scholar 

  40. W. N. Charman. Lipids, lipophilic drugs, and oral drug delivery—Some emerging concepts. J. Pharm. Sci. 89:967–978 (2000).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Dr. Hugh Wiltshire, Roche Products Ltd., U.K., for assistance with the HPLC assay.

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  1. School of Pharmacy, University College Cork, Cork, Ireland

    Brendan T. Griffin & Caitriona M. O’Driscoll

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  1. Brendan T. Griffin
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Correspondence to Brendan T. Griffin.

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Griffin, B.T., O’Driscoll, C.M. An Examination of the Effect of Intestinal First Pass Extraction on Intestinal Lymphatic Transport of Saquinavir in the Rat. Pharm Res 25, 1125–1133 (2008). https://doi.org/10.1007/s11095-007-9473-3

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