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Absorption Rate Limit Considerations for Oral Phosphate Prodrugs

Pharmaceutical Research
Publication Date
  • Biology
  • Pharmacology


Absorption Rate Limit Considerations for Oral Phosphate Prodrugs Absorption Rate Limit Considerations for Oral Phosphate Prodrugs Tycho Heimbach,1 Doo-Man Oh,2 Lilian Y. Li,1 Markus Forsberg,3 Jouko Savolainen,4 Jukka Leppa¨nen,4 Yasushi Matsunaga,5 Gordon Flynn,1 and David Fleisher1,6 Received February 19, 2003; accepted February 28, 2003 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 pro- drugs 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 �M fosphenytoin, re- spectively. Hydrocortisone’s flux did not increase with hydrocorti- sone-phosphate at 100 �M. 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 par- ent drugs transport studies should be done with albumin. KEY WORDS: absorption; caco-2; permeability; phosphate ester prodrug; protein effects. INTRODUCTION Phosphate prodrugs are often used to dev

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