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

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

1
Biopharmaceutics, Pharmaceutical Science, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
2
Discovery Pharmaceutical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
3
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
4
Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
5
Process Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
6
Toxicology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
7
Biology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
8
Formulation Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
These two authors contributed equally in the preparation of this manuscript.
Presently at PharmaSolv Consulting: sdclas@pharmasolv.com.
*
Author to whom correspondence should be addressed.
Received: 20 January 2014 / Revised: 8 February 2014 / Accepted: 12 February 2014 / Published: 24 February 2014
(This article belongs to the Collection Prodrugs: from Design to Clinic)
View Full-Text   |   Download PDF [128 KB, uploaded 24 February 2014]   |  

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. View Full-Text
Keywords: prodrugs; colonic absorption; dog colonic studies; enabling QD dosing; chemistry-enabled drug delivery; enhancing lipophilicity prodrugs; colonic absorption; dog colonic studies; enabling QD dosing; chemistry-enabled drug delivery; enhancing lipophilicity
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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.

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