Reversible inhibition of human carboxylesterases by acyl glucuronides.
Carboxylesterases hydrolyze esters, amides, and thioesters to produce carboxylic acids and resulting alcohols, amines, and thiols, respectively. Uridine 5'-diphosphate- glucuronosyltransferases are colocalized with carboxylesterases and have the potential to further metabolize carboxylic acids to acyl glucuronides, but it is currently unknown if acyl glucuronides, being esters, also interact with carboxylesterases. Objective: This study explores the ability of acyl glucuronides to act as substrates or inhibitors of human carboxylesterases 1 (hCES1) and 2 (hCES2). Methods: The stability of six acyl glucuronides in the presence of hCES1, hCES2, and buffer alone (100 mM potassium phosphate, pH 7.4, 37°C) were investigated. Reversible inhibition of 4-nitrophenyl acetate hydrolysis by the acyl glucuronides was also studied. Diclofenac-β-d-glucuronide was used to explore potential time-dependent inactivation. Results: The chemical stability half-life values for CGP 47292-β-d-glucuronide, diclofenac-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, (S)-naproxen-β-d-glucuronide, ibuprofen-β-d-glucuronide (racemic), clopidogrel-β-d-glucuronide, and valproate-β-d-glucuronide were found to be 0.252, 0.537, 0.996, 1.77, 3.67, 5.02, and 15.2 hours, respectively. Diclofenac-β-d-glucuronide, clopidogrel-β-d-glucuronide, ibuprofen-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, and (S)-naproxen-β-d-glucuronide selectively inhibited hCES1, with Ki values of 4.32 ± 0.47, 24.8 ± 4.2, 355 ± 38, 468 ± 21, 707 ± 64 µM, respectively, but did not significantly inhibit hCES2. Valproate-β-d-glucuronide and CGP 47292-β-d-glucuronide did not inhibit either hCES. Time-dependent inactivation of hCES1 by diclofenac-β-d-glucuronide was not observed. Lastly, both hCES1 and hCES2 were shown not to catalyze the hydrolysis of the acyl glucuronides studied. Conclusion: Drug-drug interaction studies may be warranted for drugs that metabolize to acyl glucuronides due to the potential inhibition of hCESs.
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alcohols (R)-naproxen-β-d-glucuronide (S)-naproxen-β-d-glucuronide ibuprofen-β-d-glucuronide (racemic) amines clopidogrel-β-d-glucuronide valproate-β-d-glucuronide thiols Diclofenac-β-d-glucuronide clopidogrel-β-d-glucuronide ibuprofen-β-d-glucuronide (R)-naproxen-β-d-glucuronide (S)-naproxen-β-d-glucuronide Uridine 5'-diphosphate Valproate-β-d-glucuronide CGP 47292-β-d-glucuronide diclofenac-β-d-glucuronide acyl glucuronides acyl glucuronides carboxylic acids esters acyl glucuronides acyl glucuronides amides esters acyl glucuronides thioesters acyl glucuronides potassium phosphate carboxylic acids 4-nitrophenyl acetate acyl glucuronides Diclofenac-β-d-glucuronide CGP 47292-β-d-glucuronide diclofenac-β-d-glucuronide acyl glucuronides Carboxylesterases hCES1 Uridine 5'-diphosphate- glucuronosyltransferases hCES2 hCES hCES1 hCES1 hCES2 hCESs carboxylesterases carboxylesterases human carboxylesterases 1 hCES1 hCES2 hCES1 hCES2 human carboxylesterases