The Potential of Flavonoids to Influence Drug Metabolism and Pharmacokinetics by Local Gastrointestinal Mechanisms

Abstract

In recent years, public and scientific interest in plant flavonoids has tremendously increased due to postulated health benefits. Whereas the amount of flavonoids ingested with the regular diet is rather low, the use of supplements enriched with these polyphenolics is becoming increasingly popular. This raises concerns about possible interactions of flavonoids with therapeutic drugs, because both are xenobiotics and, thus, share at least partially the same metabolic pathways. A number of in vitro studies have shown effects of flavonoids on enzymes involved in xenobiotic metabolism, like cytochrome P450 monooxygenases and phase II conjugation enzymes, or on membrane transporters involved in drug excretion. Several investigations have also reported changes of drug bioavailability by certain flavonoids. This article attempts to present an overview of flavonoid effects on pathways involved in drug metabolism. It focuses on phase I and phase II enzymes as well as on transporters involved in drug metabolism which are expressed in the gastrointestinal tract.

Mechanism of CYP2C9 Inhibition by Flavones and Flavonols

“…gov.cn/datasearch/face3/dir.html). Although most flavonoids are rapidly metabolized in the intestinal mucosa and the liver, and the bioavailability of flavonoids and their metabolites is generally low, with peak values of plasma concentration in the low micromolar range (Manach et al, 2005;Cermak and Wolffram, 2006), some clinical studies have demonstrated that flavonoids can affect the metabolism of other drugs (Peng et al, 2003;Rajnarayana et al, 2003;Choi et al, 2004). In the current investigation of the inhibition of CYP2C9-mediated diclofenac 4Ј-hydroxylation, we have shown that many flavonoids are potent inhibitors of CYP2C9, with K i values Յ2.2 M, and, for galangin, as low as 0.15 M. These findings raise concerns about possible drug interactions between flavonoids and the some 100 therapeutic drugs metabolized by CYP2C9 (Kirchheiner and Brockmöller, 2005).…”

“…Since then, the ability of flavonoids to inhibit isoforms of CYP450, particularly CYP1A1 and CYP1A2, has been extensively confirmed (Cermak and Wolffram, 2006). Several clinical studies have reported that some flavonoids have the capacity to alter drug metabolism in vivo (Peng et al, 2003;Rajnarayana et al, 2003;Choi et al, 2004).…”

“…Flavonols are present in a variety of fruits and vegetables, whereas flavones are mainly found in cereals and herbs (Hertog et al, 1993;Bravo, 1998;Peterson and Dwyer, 1998). In the West, the estimated daily intake of both flavonols and flavones is in the range 20 to 50 mg per day (Cermak and Wolffram, 2006). However, given the growing demand for food supplements or herbal remedies containing flavonoids, and given that in some countries flavonoids are commonly used as therapeutic agents (2008 State Food and Drug Administration RPC, http://app1.sfda.gov.…”

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

“…Many flavonoids are substrates of the most pharmacologically relevant ABC transporters, P glycoprotein/ MDR1, MRP, and BCRP [123] [124] but so far scientific effort has focused on the modulation of the transporter by flavonoids [125]. Whereas some flavonoids were shown to inhibit MDR1-mediated transport processes by directly interacting with the vicinal ATP-and steroid-binding sites [126], others (like (-) epicatechin from green tea) were shown to activate MDR1 by a heterotropic allosteric mechanism [127].…”

Oral Bioavailability and Disposition of Phytochemicals

“…For example, the oral bioavailability of biochanin A was increased approximately 2-fold when coadministered with the BCRP inhibitors quercetin and epigallocatechin-3-gallate (EGCG) in rats (Moon & Morris, 2007). However this effect may at least partially be due to inhibition of metabolizing enzymes, as there is evidence that both quercetin and the green tea polyphenols may inhibit both Phase 1 and 2 metabolism (Cermak & Wolffram, 2006). Kaempferol has also been reported to increase quercetin permeability across MDCKII-Bcrp monolayers by inhibition of Bcrpmediated quercetin efflux .…”