PT  - JOURNAL ARTICLE
AU  - Wenying Li
AU  - Weiping Zhao
AU  - Xiaohong Liu
AU  - Xiaohua Huang
AU  - Omar D. Lopez
AU  - John E. Leet
AU  - R. Marcus Fancher
AU  - Van Nguyen
AU  - Jason Goodrich
AU  - John Easter
AU  - Yang Hong
AU  - Janet Caceres-Cortes
AU  - Shu Y. Chang
AU  - Li Ma
AU  - Makonen Belema
AU  - Lawrence G. Hamann
AU  - Min Gao
AU  - Mingshe Zhu
AU  - Yue-Zhong Shu
AU  - W. Griffith Humphreys
AU  - Benjamin M. Johnson
TI  - Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine <em>δ</em>-Oxidation and Rearrangement
AID  - 10.1124/dmd.115.068866
DP  - 2016 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 809--820
VI  - 44
IP  - 6
4099  - http://dmd.aspetjournals.org/content/44/6/809.short
4100  - http://dmd.aspetjournals.org/content/44/6/809.full
SO  - Drug Metab Dispos2016 Jun 01; 44
AB  - 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.