Indiplon is hydrolyzed by arylacetamide deacetylase in human liver.
Human arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of some clinically used drugs, but the information available on its substrates is limited. To increase our knowledge of the AADAC substrates, we examined whether AADAC catalyzes the hydrolysis of indiplon, which was initially developed as a hypnotic sedative drug. It has been reported that approximately 30-40% of the administered indiplon was hydrolyzed to deacetylindiplon in humans, but the enzyme responsible for this hydrolysis had not been identified. We detected high levels of indiplon hydrolase activity in human liver microsomes (HLMs), but the levels found in human liver cytosol and plasma were scarcely detectable. Recombinant AADAC showed a high level of indiplon hydrolase activity, whereas recombinant carboxylesterase 1 (CES1) and 2 (CES2) showed marginal activity. The indiplon hydrolase activity of HLM was potently inhibited by vinblastine, a potent inhibitor of AADAC and CES2, but it was not inhibited by digitonin and telmisartan, inhibitors of CES1 and CES2, respectively. In a panel of 24 individual HLM samples, the indiplon hydrolase activities were significantly correlated with the hydrolase activities of flutamide, phenacetin, and rifampicin, which are known AADAC substrates. An HLM sample with a homozygous AADAC*3 allele, which was previously found to exhibit decreased enzyme activity, showed the lowest indiplon hydrolase activity among the 24 tested samples. Collectively, we found that human AADAC is responsible for the hydrolysis of indiplon. Thus, we can add indiplon to the list of human AADAC substrates.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Mai
M
Shimizu
Tatsuki
T
Fukami
Yusuke
Y
Ito
Takaya
T
Kurokawa
Motoki
M
Kariya
Miki
M
Nakajima
Tsuyoshi
T
Yokoi
D000328:Adult; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001711:Biotransformation; D019556:COS Cells; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013379:Substrate Specificity; D013876:Thiophenes / Q000378:metabolism*; D055815:Young Adult
D006993:Hypnotics and Sedatives; D013876:Thiophenes; D001569:Benzodiazepines; C469870:indiplon; C569302:AADAC protein, human; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase