Bioavailability and metabolism of the flavonol quercetin in the pig

Abstract

During the last years, much data pointing to putative health-promoting effects of dietary plant-derived flavonoids (stemming mainly from epidemiological and in vitro studies) have been published. Our knowledge, however, concerning the systemic availability of these substances after ingestion with food is only sketchy. In the present study, we have investigated the bioavailability of the flavonol quercetin after intravenous and oral application in pigs equipped with a permanent jugular catheter. Each animal received a single intravenous dose of quercetin (0.4 mg/kg body weight) and one week later an oral dose of 50 mg/kg. A single animal additionally received an oral dose of 500 mg/kg one week after the lower oral dose. Blood samples were drawn at defined intervals over a total period of three days following the application of quercetin. Analysis of quercetin and some of its metabolites (isorhamnetin, tamarixetin, kaempferol) in plasma samples were performed by HPLC. The calculated apparent bioavailability of free, unchanged quercetin after intake of 50 mg quercetin/kg body weight was 0.54 ± 0.19%. Bioavailability was, however, considerably increased to 8.6 ± 3.8% after additionally taking into account conjugated quercetin and further increased to 17.0 ± 7.1% by including quercetin’s metabolites. Our results further indicate, that the conjugation of orally administered quercetin with glucuronic and sulfuric acid appears to preferentially occur in the intestinal wall.

Introduction

Flavonoids are a large group of natural polyphenols that are almost ubiquitously present in the plant kingdom [1]. They are ingested by man and animals with their natural diet in various amounts. In plants and most plant-derived food flavonoids are largely present as conjugates with the flavonoid aglycon linked to a variable sugar moiety by a β-glycosidic bond [2]. More than 4000 chemically different flavonoids have been identified so far, whereby variations in the sugar moiety are mainly responsible for the large number of flavonoids in plants [3]. The structure of the aglycon is characterized by a 2-phenylbenzo-γ-pyrone modified by the subtituion patterns of the two aromatic benzene rings A and B and in the oxygen containing heterocyclic C ring (Fig. 1). Based on the substitution pattern of the ring structures flavonoids can be divided into nine main classes [4]. At the moment mainly substances out of four of these classes are considered to have effects in the mammalian organism after consumption with food; these are the anthocyanins, the isoflavones, the flavan-3-ol derivatives, including tannins and catechins, and the 4-oxo-flavonoids, e.g., the flavones and flavonols. Flavonols are characterized by a 2,3-double bond, a 4-oxo group, and a hydroxy group in position C-3 (Fig. 1).

In most plants quercetin and its sugar conjugates not only are the most abundant flavonoids but also represent the largest proportion of the flavonols therein. High concentrations can be found in tea, apples, and onions [5], [6], [7]. Kühnau [2] estimated a daily total dietary flavonoid intake in humans of approximately 1 g, whereas a recent study in Germany calculated an intake of 54 mg/day [8]. Hertog et al. [9] calculated a daily intake of quercetin of 16 mg/day. A lot of in vitro studies have reported a multitude of effects of flavonoids in various biological systems [10]. Quercetin appears to be, independent from the effect investigated and the experimental model used, one of the most potent naturally occuring flavonoids, with the procyanidins having an equal potency with respect to biological effects [11]. It has been repeatedly shown that various plant flavonoids including quercetin can inhibit several key enzymes, e.g., phospholipase A2, phosholipase C, protein kinase C, protein tyrosine kinase, lipoxygenase, cyclooxygenase, cyclic nucleotide phosphodiesterase, polymerases, reverse transcriptase, and cytochrome P-450 reductases [3]. Flavonols seem to be strong competitors for the ATP-binding site on the catalytic domaine of phosphoinositide-3-kinase, a fact which may help to understand their antiproliferative and proapoptotic properties [12]. Quercetin may also interfere in the cellular transport of xenobiotics [13]. Furthermore, quercetin has been shown to influence intestinal electrolyt transport. Whereas Cermak et al. [14] demonstrated an enhanded chloride secretion by quercetin in rat intestine, Galvez et al. [15] reported that this flavonol has some antidiarrheic activity against castor oil- and PGE2-induced diarrhea in mice in vivo.

Based on epidemiological studies, evidence has been presented indicating that flavonoids may be important health-promoting compounds in plant-derived food. Whereas the conclusion of a protective effect of plant flavonoids against coronary heart disease appears to be justified [9], [16], [17], there is presently no study showing a clear effect of flavonols against various forms of cancer [18], [19].

Although systemic availability is a crucial point for each substance supposed to have postabsorptive effects, our knowledge on the pharmacokinetics and the bioavailability of quercetin in humans and animals is still limited. There are only a few publications that indicate that the relative bioavailability of quercetin-glucosides may be greater than of the aglycon. In this context, the involvement of the intestinal sodium-glucose-cotransporter (SGLT-1) in the absorption process of the glycosides was suggested [20], [21], [22]. However, information concerning the amount of quercetin or quercetin-glycosides absorbed intact is equivocal with calculated values ranging from 0 to 52% (for review, see [23]).

The aim of the present study was to investigate the absolute bioavailability of quercetin in pigs. Furthermore, information on possible first-pass effects of orally administerd quercetin should be obtained. The pig was chosen as experimental animal because of similarities between humans and pigs concerning the anatomy and the physiology of the digestive system [24], [25].