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Xenobiotica
the fate of foreign compounds in biological systems
Volume 45, 2015 - Issue 10
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Clinical Pharmacokinetics and Metabolism

Human mass balance, metabolite profile and identification of metabolic enzymes of [14C]ASP015K, a novel oral janus kinase inhibitor

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Pages 887-902 | Received 20 Jan 2015, Accepted 04 Mar 2015, Published online: 19 May 2015
 

Abstract

1. The human mass balance of 14C-labelled ASP015K ([14C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [14C]ASP015K (100 mg, 3.7 MBq) in solution. [14C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5′-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components.

2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT).

3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.

Acknowledgements

We thank Yoshifumi Katakawa (Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc.) for his useful advice in the preparation of dosing solution. We also thank Yoshiaki Sato (ADME & Tox. Research Institute, Sekisui Medical Co., Ltd.) for conducting experiments. Finally, we thank Akio Kawamura and Takashi Usui (Drug Metabolism Research Laboratories, Astellas Pharma Inc.) for their informative discussions.

Declaration of interest

The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.

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