title: Identification of cytochrome P450 isoforms involved in the metabolism of Syl930, a selective S1PR1agonist acting as a potential therapeutic agent for autoimmune encephalitis.
abstract: Syl930 is a novel sphingosine-1-phosphate receptor subtype 1 (S1PR1) agonist for the treatment of autoimmune encephalitis with promising receptor selectivity and little risk of bradycardia. Syl930 could be reversibly converted to its phosphorylated metabolite, acting as the active form to provide therapeutic effects, but eliminated principally in the form of oxidative metabolites. The aim of the present study was to identify the cytochrome P450 isoforms (CYPs) responsible for the oxidative metabolism of Syl930. Considerable production of hydroxylated metabolite (Syl930-M1) was found in both rat blood and tissue homogenates in vivo and in vitro. Moreover, another hydroxylated metabolite, Syl930-M2, was detected in human, beagle dog and cynomolgus monkey liver microsomes with significant differences in the Km, Vmaxand CLintof the metabolites among species. CYP1A1, CYP2J2, CYP4F2 and CYP3A4 were identified to be the major CYPs mediated in the hydroxylation of Syl930 by using 14 recombinant human CYPs, selective chemical inhibitors and monoclonal antibodies against CYPs. The multiple CYPs mediated oxidation was believed to be one of the reasons for the relatively short elimination half-life of Syl930.
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Mi
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Manman
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Baolian
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: hujp@imm.ac.cn.
authors.forename: Jinping
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: yanli@imm.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy*; D050031:Hashimoto Disease / Q000188:drug therapy*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D055815:Young Adult
chemical_list: D007527:Isoenzymes; D010080:Oxazoles; D011412:Propanolamines; D049349:Receptors, Lysosphingolipid; C000590835:Syl930; D003577:Cytochrome P-450 Enzyme System
keywords: CYP450 isoforms; Hydroxylated metabolites; LC-MS/MS; Metabolism; Syl930