These observations have spurred considerable interest in the development of orexin www.selleckchem.com/products/pexidartinib-plx3397.html receptor antagonists as a potential new treatment for insomnia [6, 7]. Almorexant is the first representative of this new class of compounds, which has shown promising sleep-promoting activity in animals, healthy subjects, and patients with primary insomnia [8–10]. The pharmacokinetics of almorexant after single- and multiple-dose administration to healthy subjects have been described previously [9, 11, 12]. In brief, they are characterized by a clearance of 43 L/h, a large volume of distribution (683 L), a fast absorption (time to Cmax [tmax] ~1 h), and a rapid disposition due to
a pronounced distribution phase, with concentrations decreasing to less than 20 % of maximum plasma concentration (Cmax) 8 h after administration. P005091 clinical trial Following multiple-dose administration, steady-state concentrations were reached after 4–5 days of dosing, and accumulation was minimal. In vitro, almorexant has been shown to be an inhibitor (inhibitory constant approximately 2 μM) of cytochrome P450 (CYP) isoenzymes CYP2C9, CYP2D6, and CYP3A4 but not of other CYP isoenzymes (Actelion Pharmaceuticals, data
on file). For this reason, a drug–drug interaction study was performed in healthy subjects investigating the effect of almorexant on midazolam and simvastatin, two model substrates of CYP3A4 [13]. www.selleck.co.jp/products/cobimetinib-gdc-0973-rg7420.html This study showed that almorexant only marginally increased exposure to midazolam, but exposure to simvastatin and its hydroxyacid metabolite was increased by 3.4- and 2.8-fold, respectively [14]. The difference in sensitivity of both CYP3A4 substrates is consistent with the observation that in vitro almorexant inhibited testosterone 6β-hydroxylation but not midazolam 1′-hydroxylation (Actelion Pharmaceuticals, data on file). The anticoagulant warfarin acts by inhibiting the regeneration of vitamin K1 epoxide, which is necessary for the post-ribosomal
synthesis of vitamin K-dependent clotting factors such as factors II, VII, IX, and X. Warfarin is administered as a racemic mixture of S- and R-enantiomers. Its elimination is almost entirely by metabolism followed by urinary excretion of metabolites with minimal anticoagulation activity [15]. Warfarin is metabolized by CYP isoenzymes to inactive hydroxylated metabolites and by reductases to reduced metabolites. The S-enantiomer is primarily metabolized by CYP2C9 and less by CYP2C19 and CYP3A4, whereas the R-enantiomer is I-BET-762 mainly metabolized by CYP1A2 with a smaller contribution of CYP3A4 [16]. Warfarin has a narrow therapeutic index, and small changes in its pharmacokinetics may lead to the need for dose adaptation. The present study investigated further the drug–drug interaction potential of almorexant by studying its effects on the pharmacokinetics and pharmacodynamics of warfarin. 2 Methods 2.