Article

Characteristics of β-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats

Authors: Kai-jing Zhao1, Yang Chen1, Shi-jin Hong1, Yi-ting Yang1, Jiong Xu1, Han-yu Yang1, Liang Zhu1, Ming Liu1, Qiu-shi Xie1, Xian-ge Tang1, Ting-ting Yang1, Ya-qian Zhou1, Li Liu1, Xiao-dong Liu1
1 Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Correspondence to: Li Liu: liulee@cpu.edu.cn, Xiao-dong Liu: xdliu@cpu.edu.cn,
DOI: 10.1038/s41401-019-0218-8
Received: 16 November 2018
Accepted: 24 January 2019
Advance online: 24 February 2919

Abstract

Cinnamic acid and its analogues (pyragrel and ozagrel) undergo chain-shortened (β-oxidative) and reductive metabolism on acyl side chain. In this study, we characterized the β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes, hepatic mitochondrial, and microsomal systems. A compartmental model including parent compounds and metabolites was developed to characterize in vivo β-oxidative and reductive metabolism following an intravenous dose of parent compounds to rats. The fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred model. We showed that hepatic microsomal CYP450s did not catalyze β-oxidative or reductive metabolism of the three compounds. Similar to β-oxidation of fatty acids, β-oxidative metabolism on their acyl side chain occurred mainly in mitochondria, which was highly dependent on ATP, CoA and NAD+. Fatty acids and NADH inhibited the β-oxidative metabolism. Reductive metabolism occurred in both mitochondria and microsomes. Reduction in mitochondria was ATP-, CoA-, and NAD(P)H-dependent and reversible, which was suppressed by enoyl reductase inhibitor triclosan. Reduction in microsomes was ATP-, CoA-, and NADPH-dependent but little affected by triclosan. Both plasma concentrations of β-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental model. The estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles, implicating significance of in vitro kinetics. These findings demonstrate the roles of hepatic mitochondria and microsomes in β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.
Keywords: antiplatelet drug; cinnamic acid; pyragrel; ozagrel; drug metabolism; hepatocytes; mitochondria; microsomes; pharmacokinetics; in vitro-in vivo correlation

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