Interspecies differences in stability kinetics and plasma esterases involved in hydrolytic activation of curcumin diethyl disuccinate, a prodrug of curcumin (original) (raw)
* Corresponding authors
a Biomedicinal Chemistry Program, Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
b Natural Products for Ageing and Chronic Diseases Research Unit, Chulalongkorn University, Bangkok, Thailand
c Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
d Chulalongkorn University Drug and Health Products Innovation & Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
e Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
E-mail: pornchai.r@chula.ac.th
Fax: +66-2-254-5195
Tel: +66-2-218-8310
Abstract
The investigation of in vitro plasma metabolism of ester prodrugs is an important part of in vitro ADME assays during preclinical drug development. Here, we show that the in vitro metabolism including plasma stability and metabolizing enzymes of curcumin diethyl disuccinate (CDD), an ester prodrug of curcumin, in dog and human plasma are similar but markedly different from those in rat plasma. HPLC and nonlinear regression analyses indicated that the hydrolysis of CDD in plasma followed a consecutive pseudo-first order reaction. The rapid hydrolytic cleavage of CDD in rat, dog, and human plasma was accelerated by plasma esterases in the following order: rat ≫ human > dog. LC-Q-TOF/MS analysis showed that the cleavage of ester bonds of CDD is preferential at the phenolic ester. Monoethylsuccinyl curcumin is the only intermediate metabolite found in plasma metabolism of CDD in all tested species. Further investigation using different esterase inhibitors revealed that carboxylesterase is the major enzyme involved in the hydrolysis of CDD in rats while multiple plasma esterases play a role in dogs and humans. Thus, the difference in the hydrolysis rates and the metabolizing enzymes of CDD metabolism in rat, dog and human plasma observed here is of benefit to further in vivo studies and provides a rationale for designing ester prodrugs of CUR with esterase-specific bioactivation.
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Article information
DOI
https://doi.org/10.1039/C8RA08594C
Article type
Paper
Submitted
17 Oct 2018
Accepted
27 Jan 2019
First published
06 Feb 2019
This article is Open Access
Download Citation
RSC Adv., 2019,9, 4626-4634
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Interspecies differences in stability kinetics and plasma esterases involved in hydrolytic activation of curcumin diethyl disuccinate, a prodrug of curcumin
P. Ratnatilaka Na Bhuket, P. Jithavech, B. Ongpipattanakul and P. Rojsitthisak,RSC Adv., 2019, 9, 4626DOI: 10.1039/C8RA08594C
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