Phospho-NSAIDs have enhanced efficacy in mice lacking plasma carboxylesterase: implications for their clinical pharmacology.
OBJECTIVE
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.
Division of Cancer Prevention, Department of Medicine, Stony Brook University, HSC, T-17 Room 080, Stony Brook, NY, 11794-8173, USA.
Chi C
CC
Wong
Ka-Wing
KW
Cheng
Ioannis
I
Papayannis
George
G
Mattheolabakis
Liqun
L
Huang
Gang
G
Xie
Nengtai
N
Ouyang
Basil
B
Rigas
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000097:blood / Q000235:genetics*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010755:Organophosphates / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C553002:OXT-328; D010755:Organophosphates; D009943:Organophosphorus Compounds; C527365:phosphoaspirin; D013467:Sulindac; D002265:Carboxylic Ester Hydrolases; C545375:carboxylesterase 1, mouse; D001241:Aspirin; D007052:Ibuprofen