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European Journal of Drug Metabolism and Pharmacokinetics

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01.01.2021 | Original Research Article

Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations

verfasst von: Cheng-Cheng Shi, Yun-Qing Song, Rong-Jing He, Xiao-Qing Guan, Li-Lin Song, Shi-Tong Chen, Meng-Ru Sun, Guang-Bo Ge, Li-Rong Zhang

Erschienen in: European Journal of Drug Metabolism and Pharmacokinetics | Ausgabe 1/2021

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Abstract

Background and Objective

Rapamycin and its semi-synthetic analogues (rapalogues) are frequently used in combination with other prescribed medications in clinical settings. Although the inhibitory effects of rapalogues on cytochrome P450 enzymes (CYPs) have been well examined, the inhibition potentials of rapalogues on human esterases have not been investigated. Herein, the inhibition potentials and inhibitory mechanisms of six marketed rapalogues on human esterases are investigated.

Methods

The inhibitory effects of six marketed rapalogues (rapamycin, zotarolimus, temsirolimus, everolimus, pimecrolimus and tacrolimus) on three major esterases, including human carboxylesterases 1 (hCES1A), human carboxylesterases 2 (hCES2A) and butyrylcholinesterase (BuChE), were assayed using isozyme-specific substrates. Inhibition kinetic analyses and docking simulations were performed to investigate the inhibitory mechanisms of the rapalogues with strong hCES2A inhibition potency.

Results

Zotarolimus and pimecrolimus displayed strong inhibition of human hCES2A but these agents did not inhibit hCES1A or BuChE. Further investigation demonstrated that zotarolimus could strongly inhibit intracellular hCES2A in living HepG2 cells, with an estimated IC₅₀ value of 4.09 µM. Inhibition kinetic analyses revealed that zotarolimus inhibited hCES2A-catalyzed fluorescein diacetate hydrolysis in a mixed manner, with the K_i value of 1.61 µM. Docking simulations showed that zotarolimus could tightly bind on hCES2A at two district ligand-binding sites, consistent with its mixed inhibition mode.

Conclusion

Our findings demonstrate that several marketed rapalogues are potent and specific hCES2A inhibitors, and these agents can serve as leading compounds for the development of more efficacious hCES2A inhibitors to modulate the pharmacokinetic profiles and toxicity of hCES2A-substrate drugs (such as the anticancer agent irinotecan).

Graphic Abstract

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Titel: Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations
verfasst von: Cheng-Cheng Shi
Yun-Qing Song
Rong-Jing He
Xiao-Qing Guan
Li-Lin Song
Shi-Tong Chen
Meng-Ru Sun
Guang-Bo Ge
Li-Rong Zhang
Publikationsdatum: 01.01.2021
Verlag: Springer International Publishing
Erschienen in: European Journal of Drug Metabolism and Pharmacokinetics / Ausgabe 1/2021
Print ISSN: 0378-7966
Elektronische ISSN: 2107-0180
DOI: https://doi.org/10.1007/s13318-020-00659-9

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations

Abstract

Background and Objective

Methods

Results

Conclusion

Graphic Abstract

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Background and Objective

Methods

Results

Conclusion

Graphic Abstract

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