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Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

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Abstract

Purpose

The purpose of the study was to evaluate the metabolism, pharmacokinetics and efficacy of phospho-NSAIDs in Ces1c-knockout mice.

Methods

Hydrolysis of phospho-NSAIDs by Ces1c was investigated using Ces1c-overexpressing cells. The rate of phospho-NSAID hydrolysis was compared between wild-type, Ces1c+/− and Ces1c−/− mouse plasma in vitro, and the effect of plasma Ces1c on the cytotoxicity of phospho-NSAIDs was evaluated. Pharmacokinetics of phospho-sulindac was examined in wild-type and Ces1c−/− mice. The impact of Ces1c on the efficacy of phospho-sulindac was investigated using lung and pancreatic cancer models in vivo.

Results

Phospho-NSAIDs were extensively hydrolyzed in Ces1c-overexpressing cells. Phospho-NSAID hydrolysis in wild-type mouse plasma was 6–530-fold higher than that in the plasma of Ces1c−/− mice. Ces1c-expressing wild-type mouse serum attenuated the in vitro cytotoxicity of phospho-NSAIDs towards cancer cells. Pharmacokinetic studies of phospho-sulindac using wild-type and Ces1c−/− mice demonstrated 2-fold less inactivation of phospho-sulindac in the latter. Phospho-sulindac was 2-fold more efficacious in inhibiting the growth of lung and pancreatic carcinoma in Ces1c −/− mice, as compared to wild-type mice.

Conclusions

Our results indicate that intact phospho-NSAIDs are the pharmacologically active entities and phospho-NSAIDs are expected to be more efficacious in humans than in rodents due to their differential expression of carboxylesterases.

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Abbreviations

Ces1c:

Mouse plasma carboxylesterase isoform 1c

CES2:

Carboxylesterase 2

COX:

Cyclooxygenase

KPC:

Pancreatic carcinoma

LLC:

Lewis lung carcinoma

NSAID:

Non-steroidal anti-inflammatory drug

PLA-PEG:

Polylactic acid-polyethylene glycol

P-S:

Phospho-sulindac

P-V:

Phospho-valproic acid

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the National Institutes of Health (NIH) National Cancer Institute (NCI): Grant 5R01CA154172 and the Department of Defense (DOD): Grant W81XWH 11-1-0799. Conflict of interest. The authors have nothing to disclose except for Basil Rigas, who has an equity position in Medicon Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Division of Cancer Prevention, Department of Medicine, Stony Brook University, HSC, T-17 Room 080, Stony Brook, NY, 11794-8173, USA

    Chi C. Wong, Ka-Wing Cheng, Ioannis Papayannis, George Mattheolabakis, Liqun Huang, Gang Xie, Nengtai Ouyang & Basil Rigas

  2. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong

    Chi C. Wong

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  1. Chi C. Wong
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  2. Ka-Wing Cheng
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Correspondence to Basil Rigas.

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Wong, C.C., Cheng, KW., Papayannis, I. et al. Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology. Pharm Res 32, 1663–1675 (2015). https://doi.org/10.1007/s11095-014-1565-2

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  • DOI: https://doi.org/10.1007/s11095-014-1565-2

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