Effect of honey on naringin absorption from a decoction of the pericarps of Citrus grandis

To measure naringin/naringenin absorption of a decoction prepared from the pericarps of Citrus grandis and to investigate the effect of honey on naringin/naringenin absorption, six healthy males received 200 mL decoctions of untreated and honey-treated Pericarpium Citri Grandis in a randomized crossover design. The absorption was measured by renal recovery of naringenin glucuronides/sulfates over 48 hours. The contents of naringin/naringenin in 200 mL decoctions of untreated and honey-treated Pericarpium Citri Grandis were determined to be 261.5/23.8 mumol and 303.3/11.6 mumol, respectively. The mean cumulated renal excretion of naringenin glucuronides/sulfates after intake of these two decoctions were 74.8 mumol (26.2% of dose) and 49.8 mumol (15.8% of dose), respectively. Paired Student's t-test showed that the difference of the total renal recovery of naringin/naringenin between the two decoctions was significant. The results indicated that honey significantly reduced naringin/naringenin absorption by 33.4% in humans and suggested that honey treatment might alter the efficacy of Pericarpium Citri Grandis.     

Effects of glucose, fructose and 5-hydroxymethyl-2-furaldehyde on the presystemic metabolism and absorption of glycyrrhizin in rabbits

Our previous study reported that co-administration of honey significantly increased the serum levels of glycyrrhetic acid (GA) after oral administration of glycyrrhizin (GZ) in rabbits. The components of honey are sucrose, glucose, fructose and 5-hydroxymethyl-furaldehyde (HMF). To clarify the causative component(s) in honey that altered the metabolic pharmacokinetics of GZ, rabbits were given GZ (150 mg kg(-1)) with and without glucose (5 g/rabbit), fructose (5 g/rabbit) and HMF (1 mg kg(-1)), respectively, in crossover designs. An HPLC method was used to determine concentrations of GZ and GA in serum as well as GA and 3-dehydroglycyrrhetic acid (3-dehydroGA) in faeces suspension. A noncompartment model was used to calculate the pharmacokinetic parameters and analysis of variance was used for statistical comparison. Our results indicated that the area under curve (AUC) of GA was significantly increased by 29% when HMF was coadministered, whereas the pharmacokinetics of GZ and GA were not significantly altered by coadministration of glucose or fructose. An in-vitro study, using faeces to incubate GZ and GA individually, indicated that HMF significantly inhibited the oxidation of GA to 3-dehydroGA and this may explain the enhanced GA absorption in-vivo. It was concluded that HMF is the causative component in honey that affects the presystemic metabolism and pharmacokinetics of GZ in-vivo.     

Toxicokinetics of naringin and its metabolite naringenin after 180-day repeated oral administration in beagle dogs assayed by a rapid resolution liquid chromatography/tandem mass spectrometric method

Toxicokinetic characteristics of naringin and its metabolite naringenin were investigated in beagle dogs after oral administration of naringin at the doses of 20, 100, or 500?mg/kg/day in a repeated-dose study for 1, 30, 90, and 180 days. Plasma concentrations of naringin and naringenin were determined by a rapid resolution liquid chromatography/electrospray ionization/tandem mass spectrometric method. The results showed that no differences in systemic exposure were observed between male and female beagle dogs. Systematic exposure exhibited dose-dependent increase for both naringin and naringenin. No significant accumulations were observed. Results would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.     

Sucrose, glucose and fructose have similar genotoxicity in the rat colon and affect the metabolome.

We have shown previously that a high sucrose intake increases the background level of somatic mutations and the level of bulky DNA adducts in the colon epithelium of rats. The mechanism may involve either glucose or fructose formed by hydrolysis of sucrose. Male Big Blue rats were fed 30% sucrose, glucose, fructose or potato starch as part of the diet. Mutation rates and bulky DNA adduct levels were determined in colon and liver. The concentration of short-chain fatty acids and pH were determined in caecum, C-peptide was determined in plasma, biomarkers for oxidative damage and proliferation were determined in colon, and a metabonomic analysis was performed in plasma and urine. The sugars increased the mutation rates in colon and the bulky adduct levels in colon and liver to a similar extent. All sugars decrease the caecal concentration of acetic acid and propionic acid. The metabonomic studies indicated disturbed amino acid metabolism and decrease in plasma and urinary acetate as a common feature for all sugars and confirmed triglyceridemic effects of fructose. In conclusion, the genotoxicity may be related to the altered chemical environment in the caecum and thereby also in the colon but we found no related changes in insulin resistance or oxidative stress.     

A rapid LC/MS/MS quantitation assay for naringin and its two metabolites in rats plasma

Naringin is a flavonoid that exists in many plants and traditional Chinese medicines. In this study, a highly sensitive and specific electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed for quantification of naringin and its two metabolites, naringenin and naringenin glucuronide. Naringin and naringenin were extracted from rat plasma with ethyl acetate, using hesperidin as an internal standard. Components in the extract were separated on a 100 mm x 2.0 mm Betabasic 5 microm C18 ODS column by isocratic elution with 70% methanol. The components were analyzed in the multiple-reaction-monitoring (MRM) mode in the precursor/product ion pair of m/z 581.3/273.4 for naringin, m/z 273.4/153.1 for naringenin and m/z 611.5/303.4 for hesperidin, respectively. Linear calibration curves were obtained in the range of 5-1000 ng/ml, using 0.1 ml rat plasma. The within-day coefficients of variation (CVs) were 3.1, 1.8 and 2.2% for naringin, 3.0, 3.3, 3.1% for naringenin at 5, 50 and 500 ng/ml (n=5). The between-day CVs were 3.4, 1.7 and 4.9% for naringin and 4.0, 3.0, 4.6% for naringenin (n=5) at 5, 50 and 500 ng/ml respectively. A formulation based on PEG400 was used and orally administered to Sprague-Dawley male rats. Plasma drug concentrations were measured by this method and the pharmacokinetics was analyzed by WinNonlin computer software. Plasma concentration-time profiles of naringin were found to increase quickly and decline rapidly within 2 h and could not be detected after 24 h. Naringenin and naringenin glucuronide occurred slower and the T(max) were about 9 and 7.5 h later, respectively.     

Influence of honey on the gastrointestinal metabolism and disposition of glycyrrhizin and glycyrrhetic acid in rabbits

To investigate the effects of honey on the pharmacokinetics of glycyrrhizin and glycyrrhetic acid, administration of glycyrrhizin or glycyrrhetic acid with and without honey was carried out in rabbits in a randomized crossover design. An in vitro study using rabbit fecal flora was employed to elucidate the mechanism of the interaction. HPLC methods were used for the determination of glycyrrhizin, glycyrrhetic acid and 3-dehydroglycyrrhetic acid concentrations in serum and feces. Paired and unpaired Student's t-tests were used for statistical comparisons for in vivo and in vitro studies, respectively. Our study indicated that the area under the curve (AUC0-t) of glycyrrhetic acid was significantly enhanced by 53% when honey was concomitantly given with glycyrrhizin, whereas that of glycyrrhizin was not significantly altered. Nevertheless, lack of effect was observed when honey was concurrently given with glycyrrhetic acid. Fecal study indicated that both the hydrolysis of glycyrrhizin to glycyrrhetic acid and subsequent oxidation of glycyrrhetic acid to 3-dehydroglycyrrhetic acid were significantly affected in the presence of honey to result in more glycyrrhetic acid available for absorption. It could be concluded that honey significantly affected the gastrointestinal metabolism of glycyrrhizin and resulted in the increased glycyrrhetic acid exposure. Therefore, honey might enhance the efficacy and adverse effects of glycyrrhizin.     

UPLC-Q-TOF/MS analysis of naringin and naringenin and its metabolites in rat urine and feces after intragastric administration of alcohol extract of Exocarpium Citri grandis

To analyze naringin, naringenin and its metabolites in rat urine and feces after intragastric administration of alcohol extract of Exocarpium Citri Grandis, healthy SD rats were fed with alcohol extract of Exocarpium Citri Grandis for 3 days. On the last day, 0-24 h feces and 0-4 h, 4-8 h, 8-24 h urine were collected and analyzed by UPLC-Q-TOF/MS. The post-acquisition data were processed using Metabolynx The result is that naringin and its 6 metabolites, naringenin and its 4 metabolites were detected in the urine of rat. Meanwhile, naringin and its 3 metabolites, naringenin and its 2 metabolites were detected in the feces of rat.     

Interaction of methylparaben preservative with selected sugars and sugar alcohols

The interaction of methylparaben preservative with selected sugars (glucose, fructose, sucrose, lactose, maltose, cellobiose) and sugar alcohols (lactitol, maltitol) were demonstrated in this study. It was observed that the formation of transesterification reaction products between methylparaben and the selected sugars occurred only under mild reaction conditions (e.g., pH 7.4 at 50 degrees C ), which were confirmed by HPLC-UV studies and mass spectrometry. On the other hand, under alkaline conditions and high temperature, degradation of the sugars predominated. Because sugars could easily undergo many possible degradation reactions and isomerization including on-column anomerization, the chromatograms of the reaction products were more complicated than those obtained from sugar alcohols. Sucrose, a nonreducing sugar, was much more stable than other selected sugars. The chromatogram of the transesterification reaction products of methylparaben with sucrose clearly showed eight peaks, which were likely to correspond to the same number of hydroxyl groups of sucrose. To compare the rate of the transesterification reaction of methylparaben with sucrose to that with sorbitol, kinetic studies were carried out. Similar rate constants were observed: 5.4 x 10(-7) L mol(-1) s(-1) and 4.9 x 10(-7) L mol(-1) s(-1) for sucrose and sorbitol, respectively.     

Inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells

This study aimed to investigate the inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells. The cellular uptake of benzoic acid was examined in the presence and the absence of naringin, naringenin, morin, silybin and quercetin in Caco-2 cells. All the tested flavonoids except naringin significantly inhibited (P<0.05) the cellular uptake of [(14)C]-benzoic acid. Particularly, naringenin and silybin exhibited strong inhibition effects with IC50 values of 23.4 and 30.2 microM, respectively. Kinetic analysis indicated that the inhibition mode of naringenin and silybin on MCT1 activity was competitive with a Ki of 15-20 microM. The effect of flavonoids on the gene expression of MCT1 was also examined by using RT-PCR and western blot analysis. Results indicated that the expression level of MCT1 was not affected by the treatment with naringenin or silybin. The cellular accumulation of naringenin in Caco-2 cells was not changed in the presence of benzoic acid or L-lactic acid, implying that naringenin might not be a substrate of MCT1. In conclusion, some flavonoids appeared to be competitive inhibitors of MCT1, suggesting the potential for diet-drug interactions between flavonoids and MCT1 substrates.     

Metabolism and excretion studies of oral administered naringin, a putative antitussive, in rats and dogs

Naringin, a major active flavonone glycoside from a traditional Chinese medicine Huajuhong, has been demonstrated to have activities such as peripheral antitussive, mucoregulator and anti‐inflammatory. The purpose of this study was to elucidate the metabolism and mass balance of orally administered naringin in rats and dogs. After oral administration of naringin to rats and dogs at doses of 42 mg/kg and 12.4 mg/kg, respectively, metabolites in excreta were identified using a LC‐Q‐TOF system. The major metabolites including naringin, total naringenin (including free naringenin and its conjugates) and 4‐hydroxyphenylpropionic acid in excreta were quantified by a LC‐MS/MS system. Twenty‐two metabolites were identified in dogs and 17 metabolites were detected in rats. The observed routes of naringin metabolism were hydroxylation, methylation, acetylation, hydrogenation, deglycosylation, dehydrogenation, glucuronidation, sulfation, glucosylation, ring‐fission, oxidation, glycine conjugation and dehydroxylation. On the basis of these identified metabolites, a comprehensive metabolic pathway of naringin was proposed. About 21% of administered naringin was recovered in rat excreta in the form of naringin, total naringenin and 4‐hydroxyphenylpropionic acid, and about 60% was recovered in dog excreta. The levels of 4‐hydroxyphenylpropionic acid in excreta were higher than those of naringin and total naringenin, and the quantified metabolites were excreted more through feces, rather than urine. Most of these metabolites were excreted within 36 h post dose. The results of metabolism and excretion studies provide an explanation for future pharmacological and toxicological findings and are the groundwork for clinical studies. Copyright © 2012 John Wiley & Sons, Ltd.     

柚皮苷及其苷元柚皮素的呼吸系统药理作用研究概述

柚皮苷及其苷元柚皮素属于二氢黄酮类化合物,广泛存在于各类植物或各种中药中,具有多种生物活性,包括抗炎、抗氧化、改善糖脂代谢紊乱、神经保护、抗肝损伤、抗骨质疏松等。近年来,关于柚皮苷和柚皮素的呼吸系统药理作用备受关注。本团队系统研究了柚皮苷和柚皮素的镇咳、祛痰、抗肺部炎症等药理作用,并将柚皮苷研制成国家一类新药,目前已完成了Ⅰ期临床试验研究。本文就柚皮苷和柚皮素的镇咳、祛痰、抗肺部炎症、抗肺纤维化等呼吸系统药理作用的研究进展作一综述,以期为相关研究和临床应用提供参考。     

Effect of P-glycoprotein modulators on the pharmacokinetics of camptothecin using microdialysis.

1. By performing microdialysis, this study investigated the pharmacokinetics of unbound camptothecin in rat blood, brain and bile in the presence of P-glycoprotein mediated transport modulators (cyclosporin A, berberine, quercetin, naringin and naringenin). Pharmacokinetic parameters of camptothecin were assessed using a non-compartmental model. 2. Camptothecin rapidly crosses the blood-brain barrier (BBB) within 20 min after camptothecin administration. The disposition of camptothecin in rat bile appeared to have a slow elimination phase and a peak concentration after 20 min of camptothecin administration. The area under the concentration versus time curve (AUC) for camptothecin in bile significantly surpassed that in blood, suggesting active transport of hepatobiliary excretion. 3. In the presence of cyclosporin A camptothecin AUC, in the brain, was significantly elevated but no significant change in the presence of berberine, quercetin, naringin and naringenin. 4. With treatment by smaller doses of quercetin (0.1 mg x kg(-1)), naringin (10 mg x kg(-1)) and naringenin (10 mg x kg(-1)), they significantly diminished the camptothecin AUC in bile, but was not altered by the treatment of berberine (20 mg x kg(-1)), a higher dose of quercetin (10 mg x kg(-1)), and cyclosporin A treated (20 mg x kg(-1)) and pretreated groups. 5. The distribution ratio (AUC(bile)/AUC(blood)) of camptothecin in bile was decreased in the cyclosporin A, quercetin, naringin and naringenin treated groups. However, the distribution ratio in the brain was increased in the cyclosporin A groups, but was decreased in the groups treated with quercetin, naringin and naringenin. These results revealed that P-glycoprotein might modulate hepatobiliary excretion and BBB penetration of camptothecin.     

Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction.

Our previous studies described a newly identified potential of grapefruit juice (GFJ) in mediating pharmacokinetic drug interactions due to its capability of esterase inhibition. The current study identifies the active components in GFJ responsible for its esterase-inhibitory effect. The esterase-inhibitory potential of 10 constitutive flavonoids and furanocoumarins toward p-nitrophenylacetate (PNPA) hydrolysis was investigated. The furanocoumarins bergamottin, 6',7'-dihydroxybergamottin, and bergapten, and the glycoside flavonoids naringin and hesperidin, at concentrations found in GFJ or higher, did not inhibit the hydrolysis of PNPA by purified porcine esterase and human liver microsomes. However, the flavonoid aglycones morin, galangin, kaempferol, quercetin, and naringenin showed appreciable inhibition of PNPA hydrolysis in purified porcine esterase, and human and rat liver systems. In Caco-2 cells, demonstrated to contain minimal CYP3A activity, the permeability coefficient of the prodrugs lovastatin and enalapril was increased in the presence of the active flavonoids kaempferol and naringenin, consistent with inhibition of esterase activity. In rats, oral coadministration of kaempferol and naringenin with these prodrugs led to significant increases in plasma exposure to the active acids. In addition, in portal vein-cannulated rats, coadministration of lovastatin with kaempferol (10 mg/kg) led to a 154% and a 113% increase in the portal plasma exposure to the prodrug and active acid, respectively, compared with coadministration with water. The contribution of CYP3A inhibition was demonstrated to be minimal. Overall, a series of flavonoids present in GFJ are identified as esterase inhibitors, of which kaempferol and naringenin are shown to mediate pharmacokinetic drug interaction with the prodrugs lovastatin and enalapril due to their capability of esterase inhibition.     

Enhanced tamoxifen bioavailability after oral administration of tamoxifen in rats pretreated with naringin

The aim of this study was to investigate the effect of naringin on the bioavailability and pharmacokinetics of tamoxifen and of its metabolite, 4-hydroxytamoxifen in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined by HPLC after pretreating with naringin (1.5, 7.5, and 15 mg/kg) 30 min before orally administering tamoxifen (10 mg/kg). Compared with the control group (treated with tamoxifen alone), naringin pretreated animals showed significantly (p<0.01) increased areas under the plasma concentration-time curves (AUC) and peak tamoxifen concentrations (C_max). The absolute bioavailabilities (AB%) of tamoxifen in naringin pretreated animals were enhanced versus control (from 32.8% to 47.1%), and the relative bioavailabilities (RB%) of tamoxifen in the naringin pretreated groups were 2.02–2.88 times higher than that in the control. No significant changes in the terminal half-life (t_1/2) or T_max of tamoxifen were observed in the naringin pretreated groups. The AUCs of 4-hydroxytamoxifen after pretreating naringin were also significantly elevated (p<0.05) versus the control. But metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower. These results suggest that the enhanced bioavailability of tamoxifen in the presence of naringin might be due to the inhibition of CYP3A4 by naringin. If the results of this study are further confirmed by clinical trials, tamoxifen dosages should be adjusted to avoid potential drug interaction when tamoxifen is used clinically in combination with naringin-containing dietary supplements.     

Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man.

1. The effects of grapefruit juice and naringenin on the activity of the human cytochrome P450 isoform CYP1A2 were evaluated using caffeine as a probe substrate. 2. In vitro naringin was a potent competitive inhibitor of caffeine 3-demethylation by human liver microsomes (Ki = 7-29 microM). 3. In vivo grapefruit juice (1.2 l day-1 containing 0.5 g l-1 naringin, the glycone form of naringenin) decreased the oral clearance of caffeine by 23% (95% CI: 7%-30%) and prolonged its half-life by 31% (95% CI: 20%-44%) (n = 12). 4. We conclude that grapefruit juice and naringenin inhibit CYP1A2 activity in man. However, the small effect on caffeine clearance in vivo suggests that in general the ingestion of grapefruit juice should not cause clinically significant inhibition of the metabolism of other drugs that are substrates of CYPIA2.     

Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants

Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser).Naringin, narirutin, and prunin inhibited FEX (0.3 μM) uptake by all of the examined OATP1A2 variants in a concentration-dependent manner. Compared with those for the wild type, the inhibition constants (K_i) of naringin, narirutin, and prunin for the Ala187Thr variant were significantly increased by 3.36-fold, 7.55-fold, and 10.6-fold, respectively. Naringenin inhibited all of the OATP1A2 variants, except Ala187Thr, concentration-dependently. The order of inhibitory potency was as follows for all variants: aglycone > monosaccharide glycoside > disaccharide glycosides.These results suggest that the Ala187Thr variant is less vulnerable to inhibition by naringenin and its glycosides. Moreover, greater glycosylation of naringenin reduces its inhibitory potency against OATP1A2.     

A validated solid-phase extraction HPLC method for the simultaneous determination of the citrus flavanone aglycones hesperetin and naringenin in urine

A simple, specific, precise, accurate, and robust HPLC assay for the simultaneous analysis of hesperetin and naringenin in human urine was developed and validated. Urine samples were incubated with beta-glucuronidase/sulphatase and the analytes were isolated by solid-phase extraction using C18 cartridges and separated on a C8 reversed phase column using a mixture of methanol/water/acetic acid (40:58:2, v/v/v) at 45 degrees C. The method was found to be linear in the 50-1200 ng/ml concentration range for both hesperetin and naringenin (r > 0.999). The accuracy of the method was greater than 94.8%, while the intra- and inter-day precision for hesperetin was better than 4.9 and 8.2%, respectively and for naringenin was better than 5.3 and 7.8%, respectively. Recovery for hesperetin, naringenin and internal standard 7-ethoxycoumarin was greater than 70.9%. The method has been applied for the determination of hesperetin and naringenin in urine samples obtained from a male volunteer following a single 300 mg oral dose of each of the corresponding flavanone glycosides hesperidin and naringin. The intra- and inter-day reproducibility through enzyme hydrolysis was less than 3.9% for both total (free + conjugated) hesperetin and naringenin. Stability studies showed urine quality control samples to be stable for both hesperetin and naringenin through three freeze-thaw cycles and at room temperature for 24 h (error < or = 3.6%).     

基于HPLC-CAD的参麦颗粒中糖含量与色度值的相关性分析及糖摄入量评估

目的 建立高效液相色谱串联电喷雾检测器（HPLC-CAD）同时测定参麦颗粒中三种糖类成分含量的方法，结合色度值分析参麦颗粒色泽与糖类含量的相关性，为参麦颗粒处方制法中辅料蔗糖用量和温度控制提供依据；参考世界卫生组织（WHO）及《中国居民膳食指南》中游离糖的控制指标，评估参麦颗粒中辅料蔗糖的每日摄入量，为患者健康提供指导。方法 采用HPLC测定30批参麦颗粒的糖类成分（果糖、葡萄糖、蔗糖）含量，计算游离糖的每日摄入量及供能比；采用Adobe Photoshop对来自同一光源下的参麦颗粒进行色度值（L^*、a^*、b^*）的测定，对色度值及糖类成分进行相关性分析、聚类分析及偏最小二乘法-判别分析（PLS-DA）。结果 参麦颗粒各厂家辅料蔗糖用量均超过处方规定量，相关性分析结果显示果糖和葡萄糖的含量与色度值L*呈极显著负相关，与a^*呈极显著正相关；可根据参麦颗粒颜色初步判断果糖和葡萄糖的含量，颜色越深，颗粒越偏红、偏蓝，含量越高。30批样品按不同厂家分别聚为三类，表明不同厂家生产的参麦颗粒颜色和糖类成分含量有差异显著，颜色越深，蔗糖降解越严重。30批参麦颗粒样品的蔗糖供能比均超过世界卫生组织（WHO）及《中国居民膳食指南（2022）》中建议的10%，建议厂家开发无糖剂型。结论 所建立的糖类含量测定方法准确稳定，重复性好，为处方制法合理性提供参考，为制粒过程温度控制提供依据；通过控制蔗糖日摄入量，为患者健康状况提供指导。     

Minor effects of the citrus flavonoids naringin, naringenin and quercetin, on the pharmacokinetics of doxorubicin in rats

We investigated the effects of naringin, naringenin and quercetin on the pharmacokinetics of doxorubicin in rats. These Citrus flavonoids are known as P-glycoprotein (P-gp) inhibitors and thus suspected to interact with doxorubicin, as shown by in vitro cell studies. Plasma concentrations, tissue distribution, and the urinary and biliary excretion of doxorubicin after intravenous infusion were investigated in rats followed by oral administration of Citrus flavonoids. To evaluate the impact of the biotransformation of Citrus flavonoids on the P-gp inhibition, the inhibitory effects of quercetin and its metabolite on P-gp were compared using ex vivo analysis. Contrary to previous in vitro results, the plasma concentration, biliary and urinary clearance, and tissue distribution of doxorubicin were not altered by pre-treatment with naringin and naringenin. Biliary clearance and urinary clearance were slightly decreased by quercetin, but there was no statistical difference. The minor effects of these flavonoids may relate to their low systemic concentration, due to the biotransformation in vivo situation. S9 stability assay and calcein accumulation assay showed that quercetin was a metabolically unstable compound, and the inhibitory effect of its metabolites on P-gp was negligible. In conclusion, naringin, naringenin and quercetin did not affect the in vivo pharmacokinetics of intravenously administered doxorubicin.     

Metabolism of saikosaponin c and naringin by human intestinal bacteria

By human intestinal bacteria, saikosaponin c was transformed to four metabolites, prosaikogenin E1 (E1) prosaikogenin E2 (E2), prosaikogenin E3 (E3) and saikogenin E. Metabolic time course of saikosaponin c was as follows; in early time, saikosaponin c was converted to E1 and E2, and then these were transformed to saikogenin E via E3. Also, this metabolic pathway was similar to the metabolism of saikosaponin c by rat intestinal bacteria.Bacteroides JY-6 andBacteroides YK-4, the bacteria isolated from human intestinal bacteria, could transform saiko-saponin c to E via E1 (or E2) and E3. However, these bacteria were not able to directly transform E1 and E2 to saikogenin E. Naringin was mainly transformed to naringenin by human intestinal bacteria. The minor metabolic pathway transformed naringin to naringenin via prunin. By JY-6 or YK-4, naringin was metabolized to naringenin only via prunin.