Pharmaceuticals 2014, 7(2), 207-219; doi:10.3390/ph7020207
Article

Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization

1,†,* email, 2,†,‡email, 3email, 4email, 1email, 1email, 5email, 6email, 4email, 4email, 3email, 3email, 2email, 2email, 4email, 7email, 8email and 1email
Received: 20 January 2014; in revised form: 8 February 2014 / Accepted: 12 February 2014 / Published: 24 February 2014
(This article belongs to the Special Issue Prodrugs)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption.
Keywords: prodrugs; colonic absorption; dog colonic studies; enabling QD dosing; chemistry-enabled drug delivery; enhancing lipophilicity
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MDPI and ACS Style

Nofsinger, R.; Clas, S.-D.; Sanchez, R.I.; Walji, A.; Manser, K.; Nissley, B.; Balsells, J.; Nair, A.; Dang, Q.; Bennett, D.J.; Hafey, M.; Wang, J.; Higgins, J.; Templeton, A.; Coleman, P.; Grobler, J.; Smith, R.; Wu, Y. Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization. Pharmaceuticals 2014, 7, 207-219.

AMA Style

Nofsinger R, Clas S-D, Sanchez RI, Walji A, Manser K, Nissley B, Balsells J, Nair A, Dang Q, Bennett DJ, Hafey M, Wang J, Higgins J, Templeton A, Coleman P, Grobler J, Smith R, Wu Y. Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization. Pharmaceuticals. 2014; 7(2):207-219.

Chicago/Turabian Style

Nofsinger, Rebecca; Clas, Sophie-Dorothee; Sanchez, Rosa I.; Walji, Abbas; Manser, Kimberly; Nissley, Becky; Balsells, Jaume; Nair, Amrithraj; Dang, Qun; Bennett, David J.; Hafey, Michael; Wang, Junying; Higgins, John; Templeton, Allen; Coleman, Paul; Grobler, Jay; Smith, Ronald; Wu, Yunhui. 2014. "Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization." Pharmaceuticals 7, no. 2: 207-219.

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