Pharmaceutical Research

, Volume 15, Issue 7, pp 1012–1018 | Cite as

Evaluation of a Targeted Prodrug Strategy to Enhance Oral Absorption of Poorly Water-Soluble Compounds

  • O. Helen Chan
  • Heidi L. Schmid
  • Linda A. Stilgenbauer
  • William Howson
  • David C. Horwell
  • Barbra H. Stewart


Purpose. The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound.

Methods. Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose.

Results. Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug.

Conclusions. Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.

absorption bioavailability neurokinin solubility tachykinin targeted prodrug 


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Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • O. Helen Chan
    • 1
  • Heidi L. Schmid
    • 1
  • Linda A. Stilgenbauer
    • 1
  • William Howson
    • 2
  • David C. Horwell
    • 2
  • Barbra H. Stewart
    • 1
  1. 1.Pharmacokinetics and Drug Metabolism DepartmentParke-Davis Pharmaceutical Research, Division of Warner-Lambert CompanyAnn Arbor
  2. 2.Chemistry DepartmentParke-Davis Neuroscience Research Centre, Addenbrooke's Hospital SiteCambridgeUK

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