Phospho-NSAIDs have enhanced efficacy in mice lacking plasma carboxylesterase: implications for their clinical
Chi C Wong1, Ka-Wing Cheng, Ioannis Papayannis
1Division of Cancer Prevention, Department of Medicine, Stony Brook University, HSC, T-17 Room 080, Stony Brook, NY, 11794-8173, USA.
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.
Insights
Intact phospho-NSAIDs are active drugs, more effective in humans than rodents. Carboxylesterase 1C (Ces1c) enzyme rapidly inactivates phospho-NSAIDs, reducing their efficacy in mice.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Metabolism
Background:
- Phospho-NSAIDs are prodrugs requiring activation.
- Carboxylesterase 1C (Ces1c) is a key enzyme in drug metabolism.
- Understanding Ces1c's role is crucial for phospho-NSAID efficacy.
Purpose of the Study:
- Evaluate phospho-NSAID metabolism, pharmacokinetics, and efficacy in Ces1c-knockout mice.
- Investigate the role of Ces1c in phospho-NSAID hydrolysis and activity.
Main Methods:
- Assessed phospho-NSAID hydrolysis by Ces1c in vitro.
- Compared hydrolysis rates in wild-type and Ces1c-deficient mouse plasma.
- Examined phospho-sulindac pharmacokinetics and anti-cancer efficacy in vivo.
Main Results:
- Ces1c extensively hydrolyzed phospho-NSAIDs.
- Hydrolysis was significantly lower in Ces1c-/- mice.
- Phospho-sulindac showed reduced inactivation and enhanced anti-cancer efficacy in Ces1c-/- mice.
Conclusions:
- Intact phospho-NSAIDs are the active forms.
- Phospho-NSAIDs are likely more efficacious in humans due to lower carboxylesterase activity compared to rodents.
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