Advertisement

Pharmaceutical Research

, Volume 15, Issue 8, pp 1154–1159 | Cite as

5′-Amino Acid Esters of Antiviral Nucleosides, Acyclovir, and AZT Are Absorbed by the Intestinal PEPT1 Peptide Transporter

  • Hyo-kyung Han
  • Remco L. A. de Vrueh
  • Julie K. Rhie
  • Kuang-Ming Y. Covitz
  • Philip L. Smith
  • Chao-Pin Lee
  • Doo-Man Oh
  • Wolfgang Sadee
  • Gordon L. Amidon1
Article

Abstract

Purpose. General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water soluble amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5′-amino acid ester prodrugs of the antiviral drugs and examined the potential of amino acid esters as an effective strategy for improving oral drug absorption.

Methods. Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleo-side antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycyl ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5′-amino acid ester prodrugs was characterized in three different experimental systems; in siturat perfusion model, CHO/hPEPTl cells and Caco-2 cells.

Results. Testing 5′-amino acid ester prodrugs of acyclovir and AZT, we found that the prodrugs increased the intestinal permeability of the parent nucleoside analogue 3- to 10-fold. The dose- dependent permeation enhancement was selective for the L-amino acid esters. Competitive inhibition studies in rats and in CHO cells transfected with the human peptide transporter, hPEPTl, demonstrated that membrane transport of the prodrugs was mediated predominantly by the PEPT1 H+/dipeptide cotransporter even though these prodrugs did not possess a peptide bond. Finally, transport studies in Caco-2 cells confirmed that the 5′-amino acid ester prodrugs enhanced the transcellular transport of the parent drug.

Conclusions. This study demonstrates that L-amino acid-nucleoside chimeras can serve as prodrugs to enhance intestinal absorption via the PEPT1 transporter, providing a novel strategy for improving oral therapy of nucleoside drugs.

amino acid ester PEPT1 transporter permeability prodrugs 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    P. de Miranda and M. R. Blum. Pharmacokinetics of acyclovir after intravenous and oral administration. J. Antimicrob. Chemother. 12(suppl B):29-37 (1983).Google Scholar
  2. 2.
    M. A. Jacobson, P. de Miranda, D. M. Cederberg, T. Burnette, E. Cobb, H. R. Brodie, and J. Mills. Human pharmacokinetics and tolerance of oral ganciclovir. Antimicrob. Agents Chemother. 31:1251-4 (1987).PubMedGoogle Scholar
  3. 3.
    A. P. Waclawski and P. J. Sinko. Oral absorption of anti-acquired immune deficiency syndrome nucleoside analogues. 2. Carrier-mediated intestinal transport of stavudine in rat and rabbit preparations. J. Pharm. Sci. 85:478-85 (1996).PubMedGoogle Scholar
  4. 4.
    E. Walter, T. Kissel, and G. L. Amidon. The intestinal peptide carrier: A potential transport system for small peptide derived drugs. Adv. Drug Del. Rev. 20:33-58 (1996).Google Scholar
  5. 5.
    J. P. F. Bai, B. H. Stewart, and G. L. Amidon. Gastrointestinal Transport of Peptide and Protein Drugs and Prodrugs. Handbk. Exp. Pharmacol. 110:189-206 (1994).Google Scholar
  6. 6.
    B. H. Stewart, A. R. Kugler, P. R. Thompson, and H. N. Bockbrader. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm. Res. 10:276-281 (1993).PubMedGoogle Scholar
  7. 7.
    F. H. Leibach and V. Ganapathy. Peptide transporters in the intestine and the kidney. Annu. Rev. Nutr. 16:99-119 (1996).PubMedGoogle Scholar
  8. 8.
    P. L. Smith, E. P. Eddy, C.-P. Lee, and G. Wilson. Exploitation of the intestinal oligopeptide transporter to enhance drug absorption. Drug. Del. 1:103-111 (1993).Google Scholar
  9. 9.
    M. Hu, P. Subramanian, H. I. Mosberg, and G. L. Amidon. Use of the peptide carrier system to improve the intestinal absorption of L-α-methyldopa: carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-α-methyldopa. Pharm. Res. 6:66-70 (1989).PubMedGoogle Scholar
  10. 10.
    S. Weller, M. R. Blum, M. Doucette, T. Burnette, D. M. Cederberg, P. de Miranda, and M. L. Smiley. Pharmacokinetics of the acyclovir prodrug valaciclovir after escalating single and multiple dose administration to normal volunteers. Clin. Pharmacol. Ther. 54:595-605 (1993).PubMedGoogle Scholar
  11. 11.
    L. M. Beauchamp, G. F. Orr, P. de Miranda, T. Burnette, and T. A. Krenitsky. Amino acid ester prodrugs of acyclovir. Antiviral. Chem. Chemother. 3:157-164 (1992).Google Scholar
  12. 12.
    K. Y. Covitz, G. L. Amidon, and W. Sadée. Human dipeptide transporter, hPEPTl, stably transfected into chinese hamster ovary cells. Pharm. Res. 13:1631-1634 (1996).PubMedGoogle Scholar
  13. 13.
    O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265-275 (1951).PubMedGoogle Scholar
  14. 14.
    G. J. Marks, F. M. Ryan, I. J. Hidalgo, and P. L. Smith. Mannitol as a marker for intestinal integrity in in vitroabsorption studies. Gastroenterology 100:A697 (1991).Google Scholar
  15. 15.
    D. A. Johnson and G. L. Amidon. Determination of intrinsic membrane transport parameters from perfused intestine experiments: A boundary later approach to estimating the aqueous and unbiased membrane permeabilities. J. Theor. Biol. 131:93-106 (1988).PubMedGoogle Scholar
  16. 16.
    A. De Lean, P. J. Munson, and D. Rodbard. Simultaneous analysis of families of sigmoidgand assay and physiological dose-response curves. Am. J. of Physio. 235:E 97-102 (1978).Google Scholar
  17. 17.
    G. M. Grass and S. A. Sweetana. In vitromeasurement of gastrointestinal tissue permeability using a new diffusion cell. Pharm. Res. 5:372-376 (1988).PubMedGoogle Scholar
  18. 18.
    K. C. Meadows and J. B. Dressman. Mechanism of acyclovir uptake in rat jejunum. Pharm. Res. 7:299-303 (1990).PubMedGoogle Scholar
  19. 19.
    M. Hu. Comparison of uptake characteristics of thymidine and zidovudine in a human intestinal epithelial model system. J. Pharm. Sci. 82:829-833 (1993).PubMedGoogle Scholar
  20. 20.
    T. Okano, K. Inui, H. Maegawa, M. Takano, and R. Hori. H + coupled uphill transport of aminocephalosporins via the dipeptide transport system in rabbit intestinal brush-border membranes. J. Biol. Chem. 261:14130-4 (1986).PubMedGoogle Scholar
  21. 21.
    D. I. Friedman and G. L. Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats: enalapril and fosinopril. Pharm. Res. 6:1043-7 (1989).PubMedGoogle Scholar
  22. 22.
    J. Samanen, G. Wilson, P. L. Smith, C. P. Lee, W. Bondinell, T. Ku, G. Rhodes, and A. Nichols. Chemical approaches to improve the oral bioavailability of peptidergic molecules. J. Pharm. Pharmacol. 48:119-35 (1996).PubMedGoogle Scholar
  23. 23.
    W. Kramer, F. Girbig, U. Gutjaha, H-W. Kleemann, I. Leipe, H. Urbach, and A. Wagner. Interaction of renin inhibitors with the intestinal uptake system for oligopeptides and beta-lactam antibiotics. Biochim. Biophys. Acta. 1027:25-30 (1990).PubMedGoogle Scholar
  24. 24.
    N. Hashimoto, T. Fujioka, K. Hayashi, K. Odaguchi, T. Toyoda, M. Nakamura, and K. Hirano. Renin inhibitor: relationship between molecular structure and oral absorption. Pharm. Res. 11:1443-7 (1994).PubMedGoogle Scholar
  25. 25.
    I. J. Hidalgo, P. Bhatnagar, C. P. Lee, J. Miller, G. Cucullino and P. L. Smith. Structural requirements for interaction with the oligopeptide transporter in Caco-2 cells. Pharm. Res. 12:317-9 (1995).PubMedGoogle Scholar
  26. 26.
    H. Bundgaard. Design of prodrugs: Bioreversible derivatives for various functional groups and chemical entities, in Design of Prodrugs, H. Bundgaard, Ed. (Elsevier, Amsterdam, The Netherlands), pp. 1-92 (1995).Google Scholar
  27. 27.
    G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413-420 (1995).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Hyo-kyung Han
    • 1
  • Remco L. A. de Vrueh
    • 2
  • Julie K. Rhie
    • 1
  • Kuang-Ming Y. Covitz
    • 3
  • Philip L. Smith
    • 4
  • Chao-Pin Lee
    • 4
  • Doo-Man Oh
    • 1
  • Wolfgang Sadee
    • 3
  • Gordon L. Amidon1
    • 1
  1. 1.College of PharmacyThe University of MichiganAnn Arbor
  2. 2.Division of BiopharmaceuticsLeiden/Amsterdam Center for Drug Research, Leiden UniversityLeidenThe Netherlands
  3. 3.Department of Biopharmaceutical Sciences and Pharmaceutical ChemistryUniversity of CaliforniaSan Francisco
  4. 4.Department of Drug Delivery, Pharmaceutical TechnologiesSmith-Kline Beecham PharmaceuticalsCollegeville

Personalised recommendations