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Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark
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Molecules 2007, 12(10), 2380-2395; https://doi.org/10.3390/12102380
Received: 28 September 2007 / Revised: 29 October 2007 / Accepted: 29 October 2007 / Published: 30 October 2007
(This article belongs to the Special Issue Prodrugs)
With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37°C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 104 min at pH 7.4 and 37°C. The carbonate esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral carbonate esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the carbonate esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting. View Full-Text
Keywords: bioreversible derivatives; carbonate ester; esterase-like properties; human serum albumin; prodrug; plasma protein binding bioreversible derivatives; carbonate ester; esterase-like properties; human serum albumin; prodrug; plasma protein binding
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Ostergaard, J.; Larsen, C. Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media. Molecules 2007, 12, 2380-2395.

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