Effects of glycyrrhizin on the pharmacokinetics of nobiletin in rats and its potential mechanism

Wang, Hao; Dong, Lin; Qu, Fangfei; He, Huimin; Sun, Wei; Man, Yu-Qing; Hong-jie, Jiang

doi:10.1080/13880209.2020.1751661

Cited by 11 publications

(7 citation statements)

References 21 publications

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“…Therefore, we concluded that the strong inhibitory effect of HMF was associated with the number of hydroxyl and methoxyl groups in HMF. Previous pharmacokinetic studies demonstrated that HMF reached a high plasma concentration in rats (Singh et al, 2011; Wang et al, 2020). Structurally, we speculated that, similar to TCDD, both HMF and 1‐hydroxypyrene are composed of several six‐membered benzene rings that form a π–π or p –π conjugated system.…”

Section: Discussionmentioning

confidence: 97%

1‐Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway

Miao

Wang

et al. 2021

British J Pharmacology

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In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis.Experimental Approach: We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. Key Results:We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression.Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. Conclusion and Implications:Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.

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Section: Discussionmentioning

confidence: 97%

1‐Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway

Miao

Wang

et al. 2021

British J Pharmacology

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“…The inhibition or induction of CYP450 activity plays vital roles in the metabolism and pharmacokinetics of various drugs during drug-drug interactions [ 13 ]. For example, the co-administration of nobiletin and glycyrrhizin induced adverse interactions, which resulted in a decrease of in the plasma concentration of nobiletin due to the enhancement of CYP3A4 activity by glycyrrhizin [ 14 ]. Cornin is one of the most widely used herbs in cardiology and exerts the effects of decreasing blood pressure, reversing cardiac hypertrophy, and improving heart function [ 5 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

Zhang¹,

Zhou

et al. 2021

BMC Complement Med Ther

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Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

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“…It also induced the drugdrug interaction between other drugs. For example, the coadministration of glycyrrhizin and nobiletin led to the enhanced metabolism of nobiletin via inducing the activity of CYP3A4 (Wang et al 2020). Therefore, it is speculated that the effect of ligustrazine on the pharmacokinetics of valsartan was a result of the enhanced activity of CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interaction study between ligustrazine and valsartan in rats and its potential mechanism

Liu

Zhang

et al. 2020

Pharmaceutical Biology

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Context: Ligustrazine and valsartan are commonly used drugs in the treatment of cardiac and cardiovascular disease. Objective: The interaction between ligustrazine and valsartan was studied to investigate the effect of ligustrazine on the pharmacokinetics of valsartan. Materials and methods: The pharmacokinetics of valsartan (10 mg/kg) was investigated in Sprague-Dawley rats divided into three groups (with the pretreatment of 4 or 10 mg/kg/day ligustrazine for 10 days and without the pretreatment of ligustrazine as control) of six rats each. The in vitro experiments in rat liver microsomes were performed to explore the effect of ligustrazine on the metabolic stability of valsartan. Results: Ligustrazine changed the pharmacokinetic profile of valsartan. In the presence of 4 mg/kg ligustrazine, the AUC (0-t) (385.37 ± 93.05 versus 851.64 ± 104.26 lg/L Ã h), t 1/2 (5.46 ± 0.93 versus 6.34 ± 1.25 h), and C max (62.64 ± 9.09 versus 83.87 ± 6.15 lg/L) of valsartan was significantly decreased, and the clearance rate was increased from 10.92 ± 1.521 to 25.76 ± 6.24 L/h/kg and similar changes were observed in the group with 10 mg/kg ligustrazine (p < 0.05). The metabolic stability of valsartan was also decreased by ligustrazine as the half-life of valsartan in rat liver microsomes decreased from 37.12 ± 4.06 to 33.48 ± 3.56 min and the intrinsic clearance rate increased from 37.34 ± 3.84 to 41.40 ± 4.32 lL/min/mg protein (p < 0.05). Discussion and conclusions: Ligustrazine promoted the metabolism of valsartan via activating CYP3A4. The co-administration of ligustrazine and valsartan should be taken into account.

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Effects of glycyrrhizin on the pharmacokinetics of nobiletin in rats and its potential mechanism

Cited by 11 publications

References 21 publications

1‐Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway

1‐Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway

In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

Pharmacokinetic interaction study between ligustrazine and valsartan in rats and its potential mechanism

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