Absorption, metabolism and excretion of darexaban (YM150), a new direct factor Xa inhibitor in humans. (June 2013)

• Record Type: Journal Article
• Authors: Hashimoto, Tadashi; Suzuki, Katsuhiro; Kihara, Yukie; Iwatsubo, Takafumi; Miyashita, Aiji; Heeringa, Marten; Onkels, Hartmut; Groenendaal, Dorien; Verheggen, Frank; van Marle, Sjoerd; Usui, Takashi
• Is Part Of: Xenobiotica. Volume 43:Number 6(2013:Jun.)
• Page Start: 534
• Page End: 547
• Publication Date: 2013-06
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2012.738045
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p>1. The absorption, metabolism and excretion of darexaban (YM150), a novel oral direct factor Xa inhibitor, were investigated after a single oral administration of [<sup>14</sup>C]darexaban maleate at a dose of 60 mg in healthy male human subjects.</p> <p>2. [<sup>14</sup>C]Darexaban was rapidly absorbed, with both blood and plasma concentrations peaking at approximately 0.75 h post-dose. Plasma concentrations of darexaban glucuronide (M1), the pharmacological activity of which is equipotent to darexaban <italic>in vitro</italic>, also peaked at approximately 0.75 h.</p> <p>3. Similar amounts of dosed radioactivity were excreted via faeces (51.9%) and urine (46.4%) by 168 h post-dose, suggesting that at least approximately half of the administered dose is absorbed from the gastrointestinal tract.</p> <p>4. M1 was the major drug-related component in plasma and urine, accounting for up to 95.8% of radioactivity in plasma. The <italic>N</italic>-oxides of M1, a mixture of two diastereomers designated as M2 and M3, were also present in plasma and urine, accounting for up to 13.2% of radioactivity in plasma. In faeces, darexaban was the major drug-related component, and <italic>N</italic>-demethyl darexaban (M5) was detected as a minor metabolite.</p> <p>5. These findings suggested that, following oral administration of darexaban in humans, M1 is quickly formed during first-pass metabolism via UDP-glucuronosyltransferases, exerting its pharmacological activity in blood before being excreted into urine and faeces.</p> </abstract>