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Absorption Rate Limit Considerations for Oral Phosphate Prodrugs

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Abstract

Purpose. To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs.

Methods. Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats.

Results. Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 μM fosphenytoin, respectively. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 μM. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension.

Conclusion. Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.

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Authors and Affiliations

  1. College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109

    Tycho Heimbach, Lilian Y. Li, Gordon Flynn & David Fleisher

  2. Aventis Pharmaceuticals, 1041 Route 202-206 North, P.O. Box 6800, Bridgewater, New Jersey, 08807

    Doo-Man Oh

  3. Department of Pharmacology and Toxicology, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Markus Forsberg

  4. Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Jouko Savolainen & Jukka Leppänen

  5. Pharmaceutical Research Laboratory, Taiho Pharmaceutical Co., Ltd., Kowauchi-cho, Tokushima, 771-01, Japan

    Yasushi Matsunaga

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  1. Tycho Heimbach
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Heimbach, T., Oh, DM., Li, L.Y. et al. Absorption Rate Limit Considerations for Oral Phosphate Prodrugs. Pharm Res 20, 848–856 (2003). https://doi.org/10.1023/A:1023827017224

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