Human arylacetamide deacetylase (AADAC) plays a role in the detoxification or activation of drugs and is sometimes involved in the incidence of toxicity by catalyzing hydrolysis reactions. AADAC prefers compounds with relatively small acyl groups, such as acetyl groups. Eslicarbazepine acetate, an antiepileptic drug, is a prodrug rapidly hydrolyzed to eslicarbazepine. We sought to clarify whether AADAC might be responsible for the hydrolysis of eslicarbazepine acetate. Eslicarbazepine acetate was efficiently hydrolyzed by human intestinal and liver microsomes and recombinant human AADAC. The hydrolase activities in human intestinal and liver microsomes were inhibited by epigallocatechin gallate, a specific inhibitor of AADAC, by 82% and 88% of the control, respectively. The hydrolase activities in liver microsomes from 25 human livers were significantly correlated (r = 0.87, P < 0.001) with AADAC protein levels, suggesting that the enzyme AADAC is responsible for the hydrolysis of eslicarbazepine acetate. The effects of genetic polymorphisms of AADAC on eslicarbazepine acetate hydrolysis were examined by using the constructed recombinant AADAC variants with T74A, V172I, R248S, V281I, N366K, or X400Q. AADAC variants with R248S or X400Q showed lower activity than wild type (5% or 21%, respectively), whereas those with V172I showed higher activity than wild type (174%). Similar tendencies were observed in the other 4 substrates of AADAC; that is, p-nitrophenyl acetate, ketoconazole, phenacetin, and rifampicin. Collectively, we found that eslicarbazepine acetate is specifically and efficiently hydrolyzed by human AADAC, and several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response.

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ABBREVIATIONS: AKR, aldo-keto reductase; AOX1, aldehyde oxidase 1; AUC, area under the curve; CL int , intrinsic clearance; C max , maximum plasma concentration; DTT, dithiothreitol; HIC, human intestinal cytosol; HIM, human intestinal microsomes; HLC, human liver cytosol; HLM, human liver microsomes; HRC, human renal cytosol; HRM, human renal microsomes; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MNA, N-methylnicotinamide; MSR, methionine sulfoxide reductase; NSAID, nonsteroidal anti-inflammatory drug; SDR, short-chain dehydrogenases/reductases; TXN, thioredoxin; TXNR, thioredoxin reductase; T max , time of maximum plasma concentration This article has not been copyedited and formatted. The final version may differ from this version.