PT - JOURNAL ARTICLE AU - Ulrike Glaenzel AU - Yi Jin AU - Robert Nufer AU - Wenkui Li AU - Kirsten Schroer AU - Sylvie Adam-Stitah AU - Sjoerd Peter van Marle AU - Eric Legangneux AU - Hubert Borell AU - Alexander D. James AU - Axel Meissner AU - Gian Camenisch AU - Anne Gardin TI - Metabolism and Disposition of Siponimod, a Novel Selective S1P<sub>1</sub>/S1P<sub>5</sub> Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism AID - 10.1124/dmd.117.079574 DP - 2018 Jul 01 TA - Drug Metabolism and Disposition PG - 1001--1013 VI - 46 IP - 7 4099 - http://dmd.aspetjournals.org/content/46/7/1001.short 4100 - http://dmd.aspetjournals.org/content/46/7/1001.full SO - Drug Metab Dispos2018 Jul 01; 46 AB - Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration–time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.