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.

Jesper Ostergaard,Claus Larsen

doi:10.3390/12102380

Jesper Ostergaard, Claus Larsen

Open Access

https://doi.org/10.3390/12102380

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Journal: Molecules (Basel, Switzerland)	Publication Date: Oct 30, 2007
Citations: 73	License type: CC BY 3.0

Affiliation: University of Copenhagen

Abstract

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 degrees C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 x 10(4) min at pH 7.4 and 37 degrees 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.

Highlights

Poor pharmacokinetics, together with toxicological issues, are major causes of drug failure during early development
To assess the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving pharmacokinetics, we have studied a series of bioreversible derivatives of the model drug phenol
We present the in vitro characterization of a series of carbonate esters of phenol encompassing derivatives with fatty acid-like structures (Table 1) with respect to stability in phosphate buffer, diluted plasma and rat liver homogenate as well as initial studies on the interaction between the carbonate esters and Human serum albumin (HSA) and the implications hereof on carbonate ester reconversion rates

Summary

Introduction

Together with toxicological issues, are major causes of drug failure during early development. High affinity leads generated in drug discovery seldom possess the physicochemical properties required for transport to the site of action in the body. Bioreversible derivatization [6,7,8,9,10], i.e. the prodrug approach, allowing transient modification of pharmacokinetic properties may constitute a suitable means for improving drug performance of active agents characterized by possessing favorable receptor profiles but poor transport properties. The protracted effect of insulin fatty acid analogues is, at least in part, due to reversible binding to albumin [17,18,19]. Acylation of glucagon-like peptide-1 derivatives with fatty acids led to protracted action facilitated by albumin binding [20]. In addition to the well-known ligand binding characteristics, HSA has been associated with esterase-like properties [9,24,25,26] which may be of potential interest in the prodrug setting in relation to regeneration of parent compound

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