The characterisation of the <i>in vitro</i> metabolism and transport of 6-hydroxykynurenic acid, an important constituent of <i>Ginkgo biloba</i> extracts
Creators: name: Talap, Jadera
name: Shen, Zhuowei
name: Nie, Jing
name: Pan, Jie
name: Xu, Mingcheng
name: Zeng, Kui
name: He, Kaifeng
name: Ou, Fengting
name: He, Houhong
name: Yao, Jianbiao
name: Wang, Ruwei
name: Yu, Lushan
name: Zeng, Su
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biochemistry
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: FOS: Biological sciences
subject: Biological Sciences not elsewhere classified
subject: Mental Health
subject: Virology

description: 6-Hydroxykynurenic acid (6-HKA) is a nitrogen-containing phenolic acid compound in <i>Ginkgo biloba</i> leaves. The pharmacological activities of 6-HKA have been reported and shown that 6-HKA has the potential to become a therapeutic drug and may play an important role in the treatment of nervous system diseases. However, there are few studies on the drug metabolism and transport of 6-HKA. The aim of this study is to investigate the <i>in vitro</i> metabolism of 6-HKA and its interaction with multiple important drug transporters.The <i>in vitro</i> metabolism experiments in the present study demonstrate that 6-HKA might not undergo phase-I or phase-II metabolism in hepatic microsomes/S9 of rats. In addition, some drug transporters, including OAT1/3, OCT2, MDR1, OATP1B1, MATE1/2K and OCTN2, were investigated. The cellular uptake assays indicate that 6-HKA exhibits inhibition to the transport of classical substrates mediated by OAT3, OCT2, MATE2K and OCTN2 but has no significant effect on the transport of substrates mediated by MDR1, OAT1, OATP1B1 or MATE1. Further investigation of cellular accumulation assays shows that 6-HKA might be the substrate of OAT3, but not OCT2 or OCTN2. The bidirectional transport study suggests that 6-HKA is not a substrate of MDR1.The information about the <i>in vitro</i> metabolism of 6-HKA and the interaction between 6-HKA and some transporters will help us to better understand the pharmacokinetic properties of 6-HKA and provide reference for its pharmacodynamics, DDIs and drug-food interactions studies. 6-Hydroxykynurenic acid (6-HKA) is a nitrogen-containing phenolic acid compound in <i>Ginkgo biloba</i> leaves. The pharmacological activities of 6-HKA have been reported and shown that 6-HKA has the potential to become a therapeutic drug and may play an important role in the treatment of nervous system diseases. However, there are few studies on the drug metabolism and transport of 6-HKA. The aim of this study is to investigate the <i>in vitro</i> metabolism of 6-HKA and its interaction with multiple important drug transporters. The <i>in vitro</i> metabolism experiments in the present study demonstrate that 6-HKA might not undergo phase-I or phase-II metabolism in hepatic microsomes/S9 of rats. In addition, some drug transporters, including OAT1/3, OCT2, MDR1, OATP1B1, MATE1/2K and OCTN2, were investigated. The cellular uptake assays indicate that 6-HKA exhibits inhibition to the transport of classical substrates mediated by OAT3, OCT2, MATE2K and OCTN2 but has no significant effect on the transport of substrates mediated by MDR1, OAT1, OATP1B1 or MATE1. Further investigation of cellular accumulation assays shows that 6-HKA might be the substrate of OAT3, but not OCT2 or OCTN2. The bidirectional transport study suggests that 6-HKA is not a substrate of MDR1. The information about the <i>in vitro</i> metabolism of 6-HKA and the interaction between 6-HKA and some transporters will help us to better understand the pharmacokinetic properties of 6-HKA and provide reference for its pharmacodynamics, DDIs and drug-food interactions studies.