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Research Communication

Bioavailability of Phloretin and Phloridzin in Rats

Laboratoire des Maladies Métaboliques et des Micronutriments, I.N.R.A. de Clermont-Ferrand/Theix, 63122 Saint Genès Champanelle, France

¹To whom correspondence should be addressed. E-mail: crespy{at}clermont.inra.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Phloretin is a flavonoid found exclusively in apples and in apple-derived products where it is present as the glucosidic form, namely, phloridzin (phloretin 2'-O-glucose). In the present study, we compared the changes in plasma and urine concentrations of these two compounds in rats fed a single meal containing 0.25% phloridzin or 0.157% phloretin (corresponding to the ingestion of 22 mg of phloretin equivalents). In plasma, phloretin was recovered mainly as the conjugated forms (glucuronided and/or sulfated) but some unconjugated phloretin was also detected. By contrast, no trace of intact phloridzin was detected in plasma of rats fed a phloridzin meal. These compounds presented different kinetics of absorption; phloretin appeared more rapidly in plasma when rats were fed the aglycone than when fed the glucoside. However, whatever compound was administered, no significant difference in the plasma concentrations of total phloretin were observed 10 h after food intake. At 24 h after the beginning of the meal, the plasma concentrations of phloretin were almost back to the baseline, indicating that this compound was excreted rapidly in urine. The total urinary excretion rate of phloretin was not affected by the forms administered, and was estimated to be 8.5 µmol/24 h in rats fed phloretin or phloridzin. Thus, 10.4% of the ingested dose was recovered in urine after 24 h.

KEY WORDS: • flavonoids • phloridzin • metabolism • rats

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Flavonoids are widely distributed in edible plants (1 ). They are classified in different groups as follows: anthocyanidins, flavones, flavanones, flavonols, isoflavones and some minor flavonoids such as dihydrochalcones (2 ). The principal members of this last-mentioned category are phloretin and its glucoside, phloridzin (phloretin-2'-glucose). These compounds are found exclusively in apples, which are frequently consumed by humans. Phloridzin is present primarily in the peel of apples (80–420 mg/kg Reineta) but also in the pulp (16–20 mg/kg Reineta) (3 ); its concentration is highly dependent on the variety of apple (3 ). The most frequently described biological effect of phloridzin is its competitive inhibition of intestinal glucose uptake via sodium D-glucose cotransporter 1 (SGLT1)² (4 ). This property has led to the classification of phloridzin as an antidiabetic agent (5 –8 ). Therefore, it is of interest to study the bioavailability of these dihydroxychalcons (phloretin and phloridzin) to fully appreciate their real physiologic effect. However, until recently, only a few studies have described the metabolism of these two compounds (9 ,10 ).

Malathi and Crane (9 ) reported the presence of ß-glucosidase activity in the brush border of the hamster small intestine, which hydrolyzes phloridzin to phloretin and glucose. This enzyme, identified as lactase-phloridzin hydrolase (LPH), is also present in other species (11 ,12 ). When phloretin was administered to rats by gavage (200 mg/kg), this compound was hydrolyzed by the cecal microflora into phloretic acid and phloroglucinol, which were then detected in urine (10 ). Phloretin also was found in urine, suggesting that this compound may be absorbed before its degradation by the microflora. Nevertheless, no data are available on the characterization of the circulating forms of phloretin. Thus, the aim of the present study was to investigate the bioavailability of phloretin and its glucoside in rats.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Chemicals.

Phloridzin, ß-glucuronidase/sulfatase (Helix pomatia) were purchased from Sigma (L’Isle D’Abeau, Chesnes, France). Phloretin was purchased from Extrasynthese (Genay, France).

Animals and diets.

Male Wistar rats (n = 48; Institute Nationale de la Recherche Agronomique) weighing 160 g were housed individually in metabolic cages fitted with urine/feces separators, in temperature-controlled rooms (22°C), with a dark period from 0800 to 1600 h and free access to food throughout that period. Rats were fed a control diet with the following composition: 75.5% wheat starch, 15% casein, 3.5% mineral mixture [AIN 93M formula (13)], 1% vitamin mixture [AIN 76A formula (14)] and 5% corn oil. Rats consumed this control diet for 14 d, and were then randomly divided into three groups. Each group received 20 g of a single different experimental meal as follows: 1) the control diet, 2) the control diet supplemented with 0.25% phloridzin or 3) the control diet supplemented with 0.157% phloretin. The two supplemented meals contained 31.4 mg of phloretin equivalents. For each group of rats, food intake was controlled. Whatever the supplementation (phloretin or phloridzin), rats consumed 14 ± 0.5 g of food, corresponding to an ingestion of 22 mg of phloretin equivalents (88 mg/kg body). Rats were maintained and handled according to the recommendations of the Institutional Ethic Committee of INRA, in accordance with the decree N° 87–848.

Sampling procedure.

At 4, 10 and 24 h after the beginning of the experimental meal, six rats of each group were sampled. They were anesthetized with sodium pentobarbital (40 mg/kg body). Blood was withdrawn from the abdominal aorta into heparinized tubes. Plasma samples were acidified with 10 mmol/L acetic acid. Urine was collected for 24 h after the beginning of the meal. All of the biological samples were stored at -20°C until analysis.

HPLC analysis.

Plasma samples were acidified (to pH 4.9) with 0.1 volume of 0.58 mol/L acetic acid and incubated at 37°C for 2 h (plasma) or for 30 min (urine) with or without ß-glucuronidase/sulfatase (100 U/µL). Plasma proteins were precipitated by the addition of 500 µL of methanol/200 mmol/L HCl and the extract was centrifuged for 50 min at 14000 x g. After this extraction step, 20 µL of supernatant was injected and analyzed by HPLC. The concentrations of conjugated derivatives were estimated as the difference between the concentrations of phloretin measured before and after the enzymatic treatment. For the analysis of phloretin in plasma, plasma standards containing 0, 0.25, 0.5, 1, 5 and 10 µmol/L added phloretin were prepared. The standards were treated exactly as the samples (hydrolysis and extraction). Day-to day-variation and within-day variation for phloretin from all matrices were <10%. The recovery of phloretin from all matrices reached 97%. The limit of detection for phloretin was 25 nmol/L.

The HPLC analysis was performed using isocratic conditions (1.5 mL/min) with a 150 x 4.6 mm Hypersil BDS C18–5 µm (Life Sciences International, Cergy, France). The mobile phase consisted of 30 mmol/L NaH₂PO₄ buffer, pH 3, containing 25% acetonitrile. The detection was performed using a multielectrode coulometric detection (4-electrodes CoulArray, Eurosep, France) with potentials set at 375, 500, 600 and 700 mV.

To visualize the conjugated forms of phloretin and to detect the presence of phloridzin, the chromatographic conditions were as follows (flow rate 1 mL/min): 0–2 min, solvent A 85%/solvent B15%; 2–22 min, solvent A 85%/solvent B15% solvent A 63%/solvent B 37%; 22–28 min, solvent A 63%/solvent B 37%; 28–32 min, solvent A 63%/solvent B 37% solvent A 85%/solvent B15%; solvent A contained water and 30mmol/L NaH₂PO₄ buffer, pH 3, and solvent B, acetonitrile.

Glucose measurements.

The glucose concentration in urine, sampled from bladder, was determined by an enzymatic procedure as described by Bergmeyer et al. (15 ).

Data analysis.

Values are means ± SEM. Significance of differences between means was determined by ANOVA and the Student-Newman-Keuls multiple comparison test (Instat; GraphPad, San Diego, CA). Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
When rats were fed a meal containing phloridzin, this compound was not recovered in plasma that was not subjected to enzymatic hydrolysis. However, unconjugated phloretin was detected in the plasma of rats fed phloridzin as in those fed phloretin (9.0 ± 3.0 and 6.9 ± 0.9 µmol/L, respectively) (Fig. 1A ). After hydrolysis by ß-glucuronidase/sulfatase, the phloretin peak markedly increased (Fig. 1B ), suggesting that the major circulating forms were glucuronidated and/or sulfated derivatives of phloretin. We did not detect any methoxylated forms of phloretin in plasma. These data indicate that the nature of the circulating metabolites was independent of the administrated form of phloretin (aglycone vs. glucoside).

View larger version (33K): [in this window] [in a new window]   Figure 1. Representative chromatograms of plasma from rats fed phloretin or phloridzin before (panel A) or after (panel B) enzymatic hydrolysis by ß-glucuronidase/sulfatase. The detection was performed using multielectrode coulometric detection (4-electrodes CoulArray, Eurosep, France) with potentials set at 375, 500, 600 and 700 mV.

View larger version (22K): [in this window] [in a new window]   Figure 2. Plasma concentrations of total (unconjugated and conjugated forms) phloretin over 24 h in rats fed 0.157% phloretin (panel A) or 0.25% phloridzin (panel B). Values are means ± SEM, n = 6. *P < 0.05; (A) vs. (B).

At 24 h after food intake, the total plasma concentrations in phloretin dramatically decreased to 4.8 ± 2.1 and 7.7 ± 4.0 µmol/L after phloridzin and phloretin intake, respectively (Fig. 2) . In both cases, 14% of the total was constituted by the aglycone forms.

The urinary excretion of phloretin was measured over a 24-h period after the ingestion of each experimental meal. Excretion rates did not differ between rats fed the phloretin meal (8.5 ± 0.9 µmol/24 h) and those fed the phloridzin meal (8.2 ± 1.7 µmol/24 h). These urinary excretions corresponded to 10.4% of the ingested dose.

Because phloridzin increases glucosuria in diabetic rats (6 ), we checked whether the consumption of phloretin (22 mg) affected glucosuria. The measurements were made in urine sampled from the bladder 10 h after food intake when the total plasma concentration of phloretin was high. Glucosuria was 73.4 ± 13 µmol/L in the phloretin group and 74.0 ± 14 µmol/L in the phloridzin group, not different from that of control rats (38.8 ± 4 µmol/L; P > 0.05).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The present study clearly demonstrates that whatever form was administered (phloretin or phloridzin), their bioavailability was similar, as reflected by the absence of significant differences in the 24-h urinary excretions. However, the plasma kinetics of phloretin and phloridzin differed because phloretin appeared more rapidly in plasma when rats were fed phloretin vs. phloridzin. The high level of phloretin measured in plasma 4 h after the beginning of the meal supplemented with phloretin suggests that its absorption occurred chiefly in the small intestine. In a previous study, using an in situ intestinal perfusion model, we showed that these two compounds were absorbed in the small intestine and that phloretin was absorbed more efficiently than its glucoside (16 ).

In the plasma of rats fed a phloridzin meal, no trace of this glucoside was detected, indicating that it must be hydrolyzed, probably by LPH, before its absorption and metabolism. The analysis of plasma from rats fed a meal supplemented with phloridzin or phloretin showed that 85–95% of the circulating forms are conjugated metabolites of phloretin (glucuronides and/or sulfates) and that the remainder was present as the unconjugated form. This last result is quite surprising because when flavonoid aglycones are administered in a meal, all of the circulating forms are generally conjugated derivatives (17 –20 ). The few studies reporting the presence of unconjugated aglycone in rat plasma used gavage as the mode of administration (21 ,22 ). Such a procedure delivers a large amount of compound in short time, leading to a direct diffusion of the compound administered through the intestinal wall; thus, this does not reflect a phenomenon that could occur under physiologic conditions. Our present data suggest that when dihydrochalcones were administered in a meal, a part of the compound added to the diet could be metabolized by conjugative enzymes, and thus could be recovered intact in plasma. Moreover we did not detect any methoxylated forms of phloretin in plasma, confirming the importance of the presence of the catechol group in the methoxylation process, as previously reported (23 ,24 ).

It has been shown in vivo that some flavonoid glucosides, especially quercetin-3-O-glucose, are absorbed more rapidly than their corresponding aglycones (25 ,26 ). Different hypotheses have been proposed to explain the rapid absorption of the glucosides. Hollman et al. (25 ) suggested that the active SGLT1 could be involved in the transport of flavonol glucosides. Phloridzin blocks SGLT1 (4 ) but is not absorbed into enterocytes by this transporter (27 ). Similarly, Day et al. (28 ) proposed that if in vivo LPH is responsible for the hydrolysis of flavonoid glucosides, the proximity of the released aglycone to the membrane may facilitate the passive diffusion of the flavonoid into the enterocytes. The present study showed that when rats were fed control diets containing phloridzin or phloretin, phloretin was absorbed more rapidly than its glucoside. This is not consistent with the hypothesis of Day et al. (28 ). During the first hours after ingestion, this hydrolysis step by LPH seems to represent a bottleneck for absorption. Nevertheless, the hydrolysis did not seem to constitute a limiting step because 10 h after the beginning of the experimental meal, the plasma concentrations of phloretin did not differ in rats fed the phloridzin or phloretin meals.

At 24 h after the beginning of food intake, the plasma concentration of phloretin metabolites returned to a low level. By contrast, it has been reported that flavonoids such as quercetin or naringenin are still present at high concentrations in rat plasma 24 h after administration (19 ,29 ). This phenomenon could be due to the fact that the elimination of quercetin may be balanced by some digestive absorption, which still occurred during the postabsorptive period, and by some from enterohepatic cycling. This phenomenon allows an increase in the half-lives of these compounds. Because the conjugated forms of phloretin were quickly eliminated via the urinary route and enterohepatic cycling activity was insufficient to maintain the plasma concentration during the postabsorptive period, its half-life was decreased. We noted an enhancement in the proportion of unconjugated phloretin measured in the plasma between 4 (5%) and 24 h (14%). This rise could be due to the easier elimination of the conjugated metabolites of phloretin than of the aglycone itself.

When phloretin was administered as the aglycone or as the glucoside, 10.4% of the ingested dose was recovered in urine. Both ingested compounds were excreted to the same extent in urine. Nevertheless, phloretin was excreted more efficiently in this biological fluid, as in a previous study (4% of the ingested dose) (10 ). This excretion difference could be explained by the dose and the mode of administration (200 vs. 88 mg/kg in our study and gavage vs. meal).

The biological properties of phloridzin, which have been investigated extensively, include its ability to block the absorption of glucose by SGLT1. Moreover, phloretin inhibits the facilitated glucose transporter protein GLUT2, located on the basolateral side of the enterocytes (30 ). By this mechanism, phloretin could also limit the intestinal absorption of glucose. These properties have been demonstrated in in vivo studies using diabetic rats. Their plasma glucose concentration was normalized by treatment with phloridzin (7 ,8 ), notably by an increase of glucosuria, which limited hyperglycemia (6 ). The identification of unconjugated phloretin in plasma could be of physiologic interest. Because phloretin interacts with GLUT2, which is also present in kidney (31 ), it is conceivable that this aglycone could increase glucose urinary excretion by limiting its reabsorption.

In conclusion, the present study shows that phloretin, administered as the aglycone or as the glucoside, is absorbed rapidly in the intestine and essentially not recovered in plasma at 24 h, suggesting an efficient elimination in urine. However, it must be kept in mind that the dose of phloretin added to the experimental meals was relatively high (22 mg). It is conceivable that the bioavailability of phloretin could be modified by lower doses and especially by consuming apples. It will be interesting to evaluate the matrix effect of the fruit on phloretin bioavailability.

	FOOTNOTES

 
² Abbreviations used: GLUT, glucose transporter protein; LPH, lactase-phloridzin hydrolase; SGLT1, sodium D-glucose cotransporter 1.

Manuscript received July 3, 2001. Revision accepted September 26, 2001.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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