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Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement.
Li, Wenying; Zhao, Weiping; Liu, Xiaohong; Huang, Xiaohua; Lopez, Omar D; Leet, John E; Fancher, R Marcus; Nguyen, Van; Goodrich, Jason; Easter, John; Hong, Yang; Caceres-Cortes, Janet; Chang, Shu Y; Ma, Li; Belema, Makonen; Hamann, Lawrence G; Gao, Min; Zhu, Mingshe; Shu, Yue-Zhong; Humphreys, W Griffith; Johnson, Benjamin M.
Afiliación
  • Li W; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Zhao W; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Liu X; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Huang X; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Lopez OD; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Leet JE; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Fancher RM; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Nguyen V; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Goodrich J; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Easter J; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Hong Y; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Caceres-Cortes J; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Chang SY; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Ma L; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Belema M; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Hamann LG; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Gao M; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Zhu M; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Shu YZ; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Humphreys WG; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
  • Johnson BM; Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, W
Drug Metab Dispos ; 44(6): 809-20, 2016 06.
Article en En | MEDLINE | ID: mdl-27029743
ABSTRACT
Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Pirrolidinas / Biotransformación / Imidazoles Límite: Animals / Humans / Male Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Pirrolidinas / Biotransformación / Imidazoles Límite: Animals / Humans / Male Idioma: En Año: 2016 Tipo del documento: Article