Pharmaceutical Research

, Volume 18, Issue 9, pp 1270–1276 | Cite as

Enhanced Oral Bioavailability of 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) Through Local Inhibition of Intestinal Adenosine Deaminase

  • R. Tyler DeGraw
  • Bradley D. Anderson


Purpose. Intestinal enzyme inhibition may be an effective tool to increase the oral bioavailability of compounds that undergo first-pass intestinal metabolism. However, systemic enzyme inhibition may be undesirable and therefore should be minimized. 2-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) is an adenosine deaminase (ADA) activated prodrug of 2-β-fluoro-2′,3′-dideoxyinosine (F-ddI) with enhanced delivery to the central nervous system (CNS) that has been tested clinically for the treatment of AIDS. Unfortunately, intestinally localized ADA constitutes a formidable enzymatic barrier to the oral absorption of F-ddA. This study explores various factors involved in inhibitor selection and dosage regimen design to achieve local ADA inhibition with minimal systemic inhibition.

Methods. In situ intestinal perfusions with mesenteric vein cannulation were performed in the rat ileum to determine the lumenal disappearance and venous blood appearance of F-ddA and F-ddI. Coperfusions with the ADA inhibitor erythro9-(2-hydroxy-3-nonyl)adenine [(+)-EHNA] over a range of concentrations were used to monitor inhibitor effects on F-ddA absorption and metabolism.

Results. High concentrations of EHNA in coperfusions with F-ddA completely inhibited intestinal ADA, increasing the permeability coefficient of F-ddA by nearly threefold but producing high systemic inhibition of ADA. Mathematical models were utilized to show that in full-length intestinal perfusions an optimal log mean lumenal EHNA perfusate concentration of 0.5 μg/ml could achieve an intestinal bioavailability of 80% with <20% systemic inhibition.

Conclusions. Optimizing local enzyme inhibition may require careful selection of a suitable inhibitor, the dose of the inhibitor, and the inhibitor vs. drug absorption profiles.

F-ddA adenosine deaminase EHNA intestinal metabolism bioavailability intestinal permeability dideoxynucleosides HIV AIDS 


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  1. 1.
    T. Hasegawa, K. Juni, M. Saneyoshi, and T. Kawaguchi. Intestinal absorption and first-pass elimination of 2′,3′-dideoxynucleosides following oral administration in rats. Biol. Pharm. Bull. 19:599–603 (1996).Google Scholar
  2. 2.
    H. Suzuki and Y. Sugiyama. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur. J. Pharm. Sci. 12:3–12 (2000).Google Scholar
  3. 3.
    D. D. Shen, K. L. Kunze, and K. E. Thummel. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv. Drug Deliv. Rev. 27:99–127 (1997).Google Scholar
  4. 4.
    J. P. Shaw, C. M. Sueoko, R. Oliyai, W. A. Lee, M. N. Arimilli, C. U. Kim, and K. C. Cundy. Metabolism and pharmacokinetics of novel oral prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl] adenine (PMPA) in dogs. Pharm. Res. 14:1824–1829 (1997).Google Scholar
  5. 5.
    C. L. Zimmerman, R. P. Remmel, S. S. Ibrahim, S. A. Beers, and R. Vince. Pharmacokinetic evaluation of (−)-6-aminocarbovir as a prodrug for (−)-carbovir in rats. Drug Metab. Dispos. 20:47–51 (1992).Google Scholar
  6. 6.
    M. E. Morgan, S.-C. Chi, K. Murakami, H. Mitsuya, and B. D. Anderson. Central nervous system targeting of 2′,3′-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs. Antimicrob. Agents Chemother. 36:2156–2165 (1992).Google Scholar
  7. 7.
    B. D. Anderson, M. E. Morgan, and D. Singhal. Enhanced oral bioavailability of ddI after administration of 6-Cl-ddP, an adenosine deaminase-activated prodrug, to chronically catheterized rats. Pharm. Res. 12:1126–1133 (1995).Google Scholar
  8. 8.
    H. H. Kupferschmidt, K. E. Fattinger, H. R. Ha, F. Follath, and S. Krahenbuhl. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br. J. Clin. Pharmacol. 45:355–359 (1998).Google Scholar
  9. 9.
    J. Van Gelder, P. Annaert, L. Naesens, E. De Clercq, G. Van den Mooter, R. Kinget, and P. Augustijns. Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption: An in vitro study. Pharm. Res. 16:1035–1040 (1999).Google Scholar
  10. 10.
    C. L. Zimmerman, Y. Wen, and R. P. Remmel. First-pass disposition of (−)-6-aminocarbovir in rats: II. Inhibition of intestinal first-pass metabolism. Drug Metab. Dispos. 28:672–679 (2000).Google Scholar
  11. 11.
    D. Singhal and B. D. Anderson. Optimization of the local inhibition of intestinal adenosine deaminase (ADA) by erythro-9-(2-hydroxy-3-nonyl)adenine: enhanced oral delivery of an ADA-activated prodrug for anti-HIV therapy. J. Pharm. Sci. 87:578–585 (1998).Google Scholar
  12. 12.
    D. Singhal, N. F. Ho, and B. D. Anderson. Absorption and intestinal metabolism of purine dideoxynucleosides and an adenosine deaminase-activated prodrug of 2′,3′-dideoxyinosine in the mesenteric vein cannulated rat ileum. J. Pharm. Sci. 87:569–577 (1998).Google Scholar
  13. 13.
    J. S. Roth, C. M. McCully, F. M. Balis, D. G. Poplack, and J. A. Kelley. 2′-β-Fluoro-2′,3′-dideoxyadenosine, lodenosine, in rhesus monkeys: plasma and cerebrospinal fluid pharmacokinetics and urinary disposition. Drug Metab. Disp. 27:1128–1132 (1999).Google Scholar
  14. 14.
    J. A. Kelley, H. Ford, Jr., J. S. Roth, L. Welles, N. M. Malinowski, R. F. Little, J. A. Leitzau, L. A. Gillim, J. P. Davignon, J. S. Driscoll, and R. Yarchoan. The pharmacokinetics and oral bioavailability of lodenosine (F-ddA), a uniquely stable anti-HIV drug, in adults with sympromatic HIV infection. Int. Conf. AIDS, 12:826 (1998).Google Scholar
  15. 15.
    N. F. Ho, J. Y. Park, P. F. Ni, and W. I. Higuchi. Advancing quantitative and mechanistic approaches in interfacing gastrointestinal drug absorption studies in animals and humans. In W. Crouthamel and A. C. Sarapu (eds.), Animal Models for Oral Drug Delivery in Man: In Situ and In Vivo Approaches, APhA, Washington, DC, 1983, pp. 27–106.Google Scholar
  16. 16.
    I. Komiya, J. Y. Park, A. Kamani, N. F. H. Ho, and W. I. Higuchi. Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes. Int. J. Pharm. 4:249–262 (1980).Google Scholar
  17. 17.
    T.-X. Xiang and B. D. Anderson. Substituent contributions to the transport of substituted p-toluic acids across lipid bilayer membranes. J. Pharm. Sci. 83:1511–1518 (1994).Google Scholar
  18. 18.
    N. F. H. Ho. Biophysical kinetic modeling of buccal absorption. Adv. Drug Deliv. Rev. 12:61–97 (1993).Google Scholar
  19. 19.
    K. F. Tifton. Kinetics and enzyme inhibition studies. In M. Sandler (ed), Enzyme Inhibitors as Drugs. University Park, Baltimore, MD 1980, pp. 1–23.Google Scholar
  20. 20.
    D. H. W. Ho, C. Pincus, C. J. Carter, R. S. Benjamin, E. J. Freireich, and G. P. Bodey Sr. Distribution and inhibition of adenosine deaminase in tissues of man, rat, and mouse. Cancer Treat. Rep. 64:629–633 (1980).Google Scholar
  21. 21.
    W. Plunkett, L. Alexander, S. Chubb, and T. L. Loo. Comparison of the activity of 2′-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine in vivo. Biochem. Pharmacol. 28:201–206 (1979).Google Scholar
  22. 22.
    R. P. Agarwal, T. Spector, and J. Parks, R. E. Tight binding inhibitors-IV: Inhibition of adenosine deaminase by various inhibitors. Biochem. Pharmacol. 26:359–367 (1977).Google Scholar
  23. 23.
    R. A. Padua, J. D. Geiger, S. M. Delaney, and J. I. Nagy. Rat brain adenosine deaminase after 2′-deoxycoformycin administration: Biochemical properties and evidence for reduced enzyme levels detected by 2′-[3H]deoxycoformycin ligand binding. J. Neurochem. 58:421–429 (1992).Google Scholar
  24. 24.
    W. Plunkett and V. Gandhi. Pharmacology of purine nucleoside analogues. Hematol. Cell Ther. 38:S67–74 (1996).Google Scholar
  25. 25.
    W. D. Klohs and A. J. Kraker. Pentostatin: future directions. Pharmacol. Rev. 44:459–477 (1992).Google Scholar
  26. 26.
    W. R. McConnell, R. L. Furner, and D. L. Hill. Pharmacokinetics of 2′-deoxycoformycin in normal and L1210 leukemic mice. Drug Metab. Dispos. 7:11–13 (1979).Google Scholar
  27. 27.
    J. J. Barchi, Jr., V. E. Marquez, J. S. Driscoll, H. Ford, Jr., H. Mitsuya, T. Shirasaka, S. Aoki, and J. A. Kelley. Potential anti-AIDS drugs. Lipophilic, adenosine deaminase-activated prodrugs. J. Med. Chem. 34:1647–1655 (1991).Google Scholar
  28. 28.
    M. D. Johnson and B. D. Anderson. Localization of purine metabolizing enzymes in bovine brain microvessel endothelial cells: an enzymatic blood-brain barrier for dideoxynucleosides? Pharm. Res. 13:1881–1886 (1996).Google Scholar
  29. 29.
    T. Shirasaka, K. Murakami, H. Ford, J. A. Kelly, H. Yoshioka, E. Kojima, S. Aoki, S. Broder, and H. Mitsuya. Lipophilic halogenated congeners of 2′,3′-dideoxypurine nucleosides active against human immunodeficiency virus in vitro. Proc. Natl. Acad. Sci. USA 87:9426–9430 (1990).Google Scholar
  30. 30.
    D. Singhal. Enzymatic Barrier to Oral and Central Nervous System Delivery of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors. Ph.D. dissertation, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 1996.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • R. Tyler DeGraw
    • 1
  • Bradley D. Anderson
    • 1
  1. 1.Division of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexington

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