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Reversible Inhibitory Effects of Saturated and Unsaturated Alkyl Esters on the Carboxylesterases Activity in Rat Intestine

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Lipids

Abstract

This study was conducted to investigate the relationship between the carbon chain length/double bonds of alkyl esters and their inhibitory potency/mechanism on carboxylesterases (CESs). CESs activity was evaluated by inhibition of adefovir dipivoxil (ADV) metabolism in rat intestinal homogenates. Furthermore, the inhibitory effect of BNPP and ethyl (E)-hex-2-enoate (C8:1) on drug absorption was evaluated in situ intestinal perfusion model. The results showed that the rank order of the inhibitory potency on CESs was C10:0 > C8:0 > C6:0 > C4:0 > C12:0, C8:1 > C8:0, C6:1 > C6:0, while the esters (C14:0, C13:1, C16:0, C18:0, C17:1, C20:0) were found to have no inhibitory effect at investigated concentrations. However, the unsaturated esters (C20:1, C20:2, C20:3) displayed the inhibitory effect on CESs. Moreover, the double reciprocal plots indicated that alky esters inhibited the CESs in competitive and mixed competitive ways which were reversible. In addition, the result of most effective CESs inhibitor C8:1 from in situ experiment showed that C8:1 can inhibit the CESs-mediated intestinal metabolism and improve the drug absorption. And the inhibition had no time-dependent effect, compared with that of BNPP groups. The study suggested that alkyl esters can be served as effective and reversible CESs inhibitors, besides that their inhibitory potency/mechanism can be affected by their carbon chain length/double bonds.

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Abbreviations

ADF:

Adefovir

ADV:

Adefovir dipivoxil

BNPP:

Bis-p-nitrophenylphosphate

CESs:

Carboxylesterases

EE:

Ethyl (E)-hex-2-enoate

LDH:

Lactate dehydrogenase

Mono-ADV:

Mono-(POM) PMEA

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Acknowledgments

We thank Mrs Dan Li for help on calculating K i/K i′ values by offering the GraphPad Prism 4.00 (GraphPad Software, San Diego California, USA). This work was supported by the National Natural Sciences Foundation of China (No. 30701054) and National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (No. 2009ZX09301-001). This work was also supported in part by the National Basic Research Program of China (No. 2009CB930300).

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Authors and Affiliations

  1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Ping Li, Chun-liu Zhu, Xin-xin Zhang, Li Gan, Hong-zhen Yu & Yong Gan

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  1. Ping Li
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  2. Chun-liu Zhu
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Correspondence to Yong Gan.

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Li, P., Zhu, Cl., Zhang, Xx. et al. Reversible Inhibitory Effects of Saturated and Unsaturated Alkyl Esters on the Carboxylesterases Activity in Rat Intestine. Lipids 45, 603–612 (2010). https://doi.org/10.1007/s11745-010-3434-z

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