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

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- to 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.

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

“…Additionally, the DEPs could influence other biological activity of T 89 in different ways. For example, Mcee gene provides instructions for making an enzyme called methylmalonyl CoA epimerase, which converts one form of the molecule methylmalonyl CoA to another, while Ces1c is responsible for the hydrolysis of ester- and amide-bond-containing xenobiotics and drugs ( Wong et al, 2015 ; Pan et al, 2017 ). Acaa2 catalyzes the last step of the mitochondrial fatty acid β-oxidation spiral and has been shown to be a functional BCL2-interacting protein 3 binding partner ( Cao et al, 2008 ), which provides a possible link between fatty acid metabolism and cell apoptosis.…”

Syntheses and cytotoxicity of phosphatidylcholines containing ibuprofen or naproxen moieties

“…In recent years, many NSAID derivatives have been found to exhibit similar activities but with less side effects than standard drugs. From these, noteworthy are the nitric oxide-releasing prodrugs of NSAIDs (NO-NSAIDs) 10,11 and the derivatives of NSAIDs with phosphate moieties (phospho-NSAIDs) 12 . Moreover, it has been reported that phospho-NSAIDs are safer than normal drugs because of their reduced gastrointestinal toxicity 13 .…”

“…Moreover, it has been reported that phospho-NSAIDs are safer than normal drugs because of their reduced gastrointestinal toxicity 13 . In addition to their anti-inflammatory properties, it has been found that phospho-NSAIDs exhibit anticancer properties against colon and breast cancer 12,14–16 .…”

Reaction of 2‐Imino‐2H‐chromene‐3‐carboxamide with Phosphorus Isothiocyanates: First Synthesis of Novel Chromeno[2,3‐d]pyrimidinyl and Bis(chromeno[2,3‐d]pyrimidinyl)phosphines and Chromeno[2′,3′:4,5]pyrimido[2,1‐d][1,3,5,2]triazaphosphinine

“…On the other hand, phosphorus‐containing compounds continue to attract a great interest because of the diversity of pharmacological activities, especially when they are associated with different heterocycles . For example, they were used as antitumor , antineoplastic , anti‐inflammatory , and antimicrobial agents . In our recent article , we studied the chemical reactivity of 2‐imino‐2 H ‐chromene‐3‐carboxamide ( 1 ) toward some phosphorus sulfides, which led to the formation of 2‐sulfido‐2,3‐dihydro‐4 H ‐chromeno[2,3‐ d ][1,3,2]diazaphosphinines.…”