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Different inhibitory effects in rat and human carboxylesterases
Shiori Takahashi1, Miki Katoh, Takashi Saitoh
1Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakumamachi, Kanazawa 920-1192, Japan.
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|February 20, 2009
Summary
This study investigated carboxylesterase (CES) inhibition across species and tissues. We found significant species differences in CES inhibition, crucial for prodrug development and understanding drug interactions.
Area of Science:
- Pharmacology and Toxicology
- Drug Metabolism and Pharmacokinetics
Background:
- In vitro inhibition studies are vital for predicting drug-drug interactions and aiding drug development.
- Carboxylesterase (CES) activity profiles and species/tissue-specific inhibition remain incompletely understood.
Purpose of the Study:
- To investigate the inhibitory effects of various drugs on carboxylesterase (CES) activity.
- To determine species and tissue differences in CES inhibition.
- To elucidate inhibition constants (K(i) values) and patterns for potent inhibitors.
Main Methods:
- Measured inhibitory effects of 15 drugs and 1 compound on human and rat liver/jejunum microsomes and cytosol.
- Determined inhibition constants (K(i) values) and inhibition patterns for strong inhibitors.
- Utilized imidapril and irinotecan hydrochloride (CPT-11) as substrates, catalyzed by CES1 and CES2 respectively.
Main Results:
- Imidapril hydrolysis in human liver was strongly inhibited by nordihydroguaiaretic acid (NDGA) and procainamide, with similar profiles in rat liver.
- NDGA showed a 30-fold higher K(i) in human liver microsomes compared to rat liver microsomes.
- CPT-11 hydrolysis was minimally inhibited, with physostigmine exhibiting a 10-fold lower K(i) in human jejunum cytosol versus rat jejunum cytosol.
Conclusions:
- Significant species differences in carboxylesterase (CES) inhibition were identified between humans and rats.
- Inhibitory profiles for CES were found to be similar between liver and jejunum tissues within species.
- These findings provide valuable insights for prodrug development and predicting drug-drug interactions.
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