Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Naringin in Aged Rats

Zeng, Xuan; Su, Weiwei; Zheng, Yonghua; He, Yudong; He, Yan; Rao, Hongyu; Peng, Wei; Yao, Hongliang

doi:10.3389/fphar.2019.00034

Cited by 82 publications

(66 citation statements)

References 52 publications

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“…The absolute bioavailability of naringin was 44.1% for rats and 34.4% for dogs, indicating a substantial first-pass effect of naringin in these animals. Moreover, compared with the report in aged rats (Zeng et al, 2019), the pharmacokinetic parameters of females were similarly significantly higher than those of males in rats and humans that was likely due to gender-related differences of CYP (Scandlyn et al, 2008).…”

Section: Pharmacokinetic Characteristics and Species Differencescontrasting

confidence: 64%

“…In previous naringin excretion studies in rats and dogs, Liu et al reported cumulative excretion percentage of 21% for rats and 60% for dogs in the forms of naringin, naringenin, and 4hydroxyphenylpropionic acid (Liu M. et al, 2012); Zeng et al presented a cumulative excretion percentage of 19% in the forms of naringin and naringenin, and 98% for aged rats in the forms of naringin, naringenin, and 4-hydroxyphenylpropionic acid (Zeng et al, 2019). In our clinical studies, the cumulative excretion percentage of the dose was less than 20% in the forms of naringin and naringenin.…”

Section: Excretion and Species Differencesmentioning

confidence: 99%

“…With the exception of methods available in the literature on the analysis of rat plasma (Tsai and Tsai, 2012;Wen et al, 2012;Tong et al, 2012;Li S. Q. et al, 2013;Jin et al, 2015;Lu et al, 2015;Zeng et al, 2018;Zeng et al, 2019) and human plasma and urine (Ishii et al, 2000;Xiong et al, 2014), only a few methods are reported to analyze naringin and naringenin in other types of biological matrices in rats, dogs, and humans. The present study reports the analysis of naringin and naringenin in rat, dog, and human plasma and human urine and feces.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species

et al. 2020

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Background: Pharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development. Methods: Separate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry. Results: The pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin.

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Section: Pharmacokinetic Characteristics and Species Differencescontrasting

confidence: 64%

Section: Excretion and Species Differencesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species

et al. 2020

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“…38 Further, we measured serum naringenin concentrations following hydrolysis of the conjugated form; however, the method provides an estimation of serum naringenin concentrations. 15,16,20,26,40 Little is known about tissue uptake and disposition of flavonoid metabolites in humans, which is important for the effects of naringenin on cell and tissue function. 41 In rodent studies, dosing with naringenin or naringin produced inconsistent results.…”

Section: Resultsmentioning

confidence: 99%

“…Although it has been suggested that the naringenin metabolites appearing in circulation are treated by the body as xenobiotics and are removed from the system, analysis of the serum concentrations provides valuable information on the pharmacokinetic profile of naringenin . Further, we measured serum naringenin concentrations following hydrolysis of the conjugated form; however, the method provides an estimation of serum naringenin concentrations …”

Section: Discussionmentioning

confidence: 99%

Safety and pharmacokinetics of naringenin: A randomized, controlled, single‐ascending‐dose clinical trial

Rebello

Beyl

Lertora

et al. 2019

Diabetes Obesity Metabolism

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Aims To evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole‐orange (Citrus sinensis) extract. Methods and methods In a single‐ascending‐dose randomized crossover trial, 18 adults ingested doses of 150 mg (NAR150), 300 mg (NAR300), 600 mg (NAR600) and 900 mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash‐out period of at least 1 week. Blood safety markers were evaluated pre‐dose and 24 hours post‐dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150 and NAR600. Four‐ and 24‐hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed‐effects linear model. Results There were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76 ± 7.88 μM (NAR150) and 48.45 ± 7.88 μM (NAR600); time to peak: 3.17 ± 0.74 hours (NAR150) and 2.41 ± 0.74 hours (NAR600); area under the 24‐hour concentration–time curve: 67.61 ± 24.36 μM × h (NAR150) and 199.05 ± 24.36 μM × h (NAR600); and apparent oral clearance: 10.21 ± 2.34 L/h (NAR150) and 13.70 ± 2.34 L/h (NAR600). Naringenin half‐life was 3.0 hours (NAR150) and 2.65 hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67 ± 5.74 μM (4 hours) and 0.35 ± 0.30 μM (24 hours). After NAR900 ingestion, serum concentrations were 43.11 ± 5.26 μM (4 hours) and 0.24 ± 0.30 μM (24 hours). Conclusions Ingestion of 150 to 900 mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 μM) is effective in primary human adipocytes, ingestion of 300 mg naringenin twice/d will likely elicit a physiological effect.

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Shatianyu dietary fiber (Citrus grandis L. Osbeck) promotes the production of active metabolites from its flavonoids during in vitro colonic fermentation

Deng,

Ye,

Zhang

et al. 2024

J Sci Food Agric

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BACKGROUNDRecent studies reveal that dietary fiber (DF) might play a critical role in the metabolism and bioactivity of flavonoids by regulating gut microbiota. We previously found that Shatianyu (Citrus grandis L. Osbeck) pulp was rich in flavonoids and DF, and Shatianyu pulp flavonoid extracts (SPFEs) were dominated by melitidin, obviously different from other citrus flavonoids dominated by naringin. The effects of Shatianyu pulp DF (SPDF) on the microbial metabolism and bioactivity of SPFEs is unknown.RESULTSAn in vitro colonic fermentation model was used to explore the effects of SPDF on the microbial metabolism and antioxidant activity of SPFEs in the present study. At the beginning of fermentation, SPDF promoted the microbial degradation of SPFEs. After 24 h‐fermentation, the supplemented SPFEs were almost all degraded in SPFEs group, and the main metabolites detected were the dehydrogenation, hydroxylation and acetylation products of naringenin, the aglycone of the major SPFEs components. However, when SPFEs fermented with SPDF for 24 h, 60.7% of flavonoid compounds were retained, and SPFEs were mainly transformed to the ring fission metabolites, such as 3‐(4‐hydroxyphenyl) propionic acid, 3‐phenylpropionic acid and 3‐(3‐hydroxy‐phenyl) propionic acid. The fermentation metabolites of SPFEs showed stronger antioxidant activity than the original ones, with a further increase in SPDF supplemented group. Furthermore, SPFEs enriched microbiota participating in the deglycosylation and dehydrogenation of flavonoids, while co‐supplementation of SPDF and SPFEs witnessed the bloom of Lactobacillaceae and Lactobacillus, contributing to the deglycosylation and ring fission of flavonoids.CONCLUSIONSDPF promote SPFEs to transform to active metabolites probably by regulating gut microbiota. © 2023 Society of Chemical Industry.

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Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Naringin in Aged Rats

Cited by 82 publications

References 52 publications

Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species

Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species

Safety and pharmacokinetics of naringenin: A randomized, controlled, single‐ascending‐dose clinical trial

Shatianyu dietary fiber (Citrus grandis L. Osbeck) promotes the production of active metabolites from its flavonoids during in vitro colonic fermentation

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