In vitro metabolism of indiplon and an assessment of its drug interaction potential.
This study was designed to study the in vitro metabolism of indiplon, a novel hypnotic agent, and to assess its potential to cause drug interactions. In incubations with pooled human liver microsomes, indiplon was converted to two major, pharmacologically inactive metabolites, N-desmethyl-indiplon and N-desacetyl-indiplon. The N-deacetylation reaction did not require NADPH, and appeared to be catalyzed by organophosphate-sensitive microsomal carboxylesterases. The N-demethylation of indiplon was catalyzed by CYP3A4/5 based on the following observations: (1) the sample-to-sample variation in N-demethylation of indiplon ([S] = 100 microM) in a bank of human liver microsomes was strongly correlated with testosterone 6beta-hydroxylase (CYP3A4/5) activity (r(2) = 0.98), but not with any other CYP enzyme; (2) recombinant CYP1A1, CYP1A2, CYP3A4, CYP3A5 and CYP3A7 had the ability to catalyze this reaction; (3) the N-demethylation of indiplon was inhibited by CYP3A4/5 inhibitors (ketoconazole and troleandomycin), but not by a CYP1A2 inhibitor (furafylline). In pooled human liver microsomes, indiplon exhibited a weak capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5 and carboxylesterase (p-nitrophenylacetate hydrolysis) activities (IC50 >/= 20 microM). Clinical data available on indiplon support the conclusions of this paper that the in vitro metabolism of indiplon is catalyzed by multiple enzymes, and indiplon is a weak inhibitor of human CYP enzymes.
Madan
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Neurocrine Biosciences, Inc., San Diego, CA 92130, USA. amadan@neurocrine.com
Fisher
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A
Jin
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Chapman
D
D
Bozigian
H P
HP
D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D013876:Thiophenes; D001569:Benzodiazepines; C469870:indiplon; D002265:Carboxylic Ester Hydrolases