Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity

Coldham, N. G.; Zhang, Aiqin; Key, Pauline; Sauer, Maurice J.

doi:10.1007/bf03192335

Cited by 58 publications

(63 citation statements)

References 30 publications

(28 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The authors of a study investigating the absolute bioavailability of genistein in rats noticed a marked sex difference with regard to bioavailability of this isoflavone. After oral administration of 15 µmol genistein/kg BW, bioavailability of the unchanged isoflavone was 6.8% in male and 14.6% in female rats [46].…”

Section: Absorption and Bioavailability Of Flavo-noidsmentioning

confidence: 97%

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

Cermak¹,

Wolffram²

2006

CDM

109

View full text Add to dashboard Cite

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.

show abstract

Section: Absorption and Bioavailability Of Flavo-noidsmentioning

confidence: 97%

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

Cermak¹,

Wolffram²

2006

CDM

109

View full text Add to dashboard Cite

show abstract

“…However, an ϳ10-fold increase in exposure levels of genistein conjugates did not appear to correlate with a slight increase in aglycone (Ͻ2-fold compared with that in WT mice) in Bcrp1 knockout mice. More importantly, numerous previous studies showed that genistein is a highly permeable compound and has good oral absorption (Ͼ50%) in vivo (Coldham and Sauer, 2000;Coldham et al, 2002;Chen et al, 2005a;Zhou et al, 2008). Impaired BCRPmediated efflux of genistein aglycone cannot explain the ϳ6-fold increase of oral bioavailability of total genistein in Bcrp1 knockout mice, because the efflux ratio of genistein in a pair of BCRP/Bcrpoverexpressed cell lines were less than 2.5.…”

Section: Introductionmentioning

confidence: 96%

“…Genistein, a plant phenolic and one of the most commonly consumed phytoestrogens, has been extensively studied because of its pharmacological and beneficial effects (Banerjee et al, 2008;Yang et al, 2012), however, with the realization that the full biological potential of genistein (i.e., aglycone) is severely hampered by its extensive metabolism into glucuronide and sulfate conjugates in humans after oral administration (Shelnutt et al, 2000;Coldham et al, 2002;Gu et al, 2006;Hosoda et al, 2010). On the other hand, although generally less active than the aglycone, genistein glucuronides retain the ability to prevent lipid oxidation and possess modest activity to enhance human natural killer cells at nutritionally relevant concentrations (Zhang et al, 1999b;Kgomotso et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein

et al. 2012

View full text Add to dashboard Cite

ABSTRACT:It was recently proposed that the improved oral bioavailability of genistein aglycone and conjugates in Bcrp1(؊/؊) mice is mainly due to increased intestinal absorption of aglycone and subsequent elevated exposure to conjugation enzymes. Here we tested this proposed mechanism and found that intestinal absorption of genistein aglycone did not increase in Bcrp1(؊/؊) mice compared with wild-type mice using an in situ mouse intestinal perfusion model and that inhibition of breast cancer resistance protein (BCRP) in Caco-2 cells also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5-to 10-fold increases in exposures of conjugates and somewhat lower fold increases (<2-fold) in exposures of aglycone were apparent after both oral and intraperitoneal administration in Bcrp1(؊/؊) mice. In contrast, the intestinal and biliary excretion of genistein conjugates significantly decreased in Bcrp1(؊/؊) mice without corresponding changes in aglycone excretion. Likewise, inhibition of BCRP functions in Caco-2 cells altered polarized excretion of genistein conjugates by increasing their basolateral excretion. We further found that genistein glucuronides could be hydrolyzed back to genistein, whereas sulfates were stable in blood. Because genistein glucuronidation rates were 110% (liver) and 50% (colon) higher and genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1(؊/؊) mice, the changes in genistein exposures are not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma area under the curve of its conjugates in Bcrp1(؊/؊) mice is due to altered distribution of genistein conjugates to the systemic circulation.

show abstract

“…Currently, several clinical trials are ongoing to test the anticancer efficacy of soy isoflavones and green tea, both of which contain flavonoids as the active ingredients (Crowell, 2005). A major impediment to the development of flavonoids is their poor bioavailabilities, which are usually approximately 3 to 5% (Coldham et al, 2002). Poor bioavailabilities make it more difficult to test flavonoids in a clinical setting because it requires a large number of subjects because exposure levels are going to be highly variable across the population.…”

mentioning

confidence: 99%

Disposition of Flavonoids via Enteric Recycling: UDP-Glucuronosyltransferase (UGT) 1As Deficiency in Gunn Rats Is Compensated by Increases in UGT2Bs Activities

Wang¹,

Kulkarni²,

Tang³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Flavonoids have poor bioavailabilities largely because of metabolism via UDP-glucuronosyltransferases (UGTs). This study aims to further understand the functions of UGT in metabolizing genistein and apigenin, two compounds metabolized more extensively in the gut than in the liver. Because Gunn rats are deficient in UGT1As, we determined whether this deficiency would result in less flavonoid glucuronidation, using rat intestinal perfusion model and microsomes prepared from rat liver and intestine. In yeast-expressed rat UGT isoforms, rat UGT1A isoforms (especially UGT1A7) were mainly responsible for flavonoid metabolism. In perfusion studies, the two flavonoids were rapidly absorbed at comparable rates, but the intestinal excretions of glucuronides in Gunn rats compared with Wistar rats were not only comparable for genistein but also were higher (p Ͻ 0.05) for apigenin, suggesting up-regulation of UGT isoforms in Gunn rats. To determine the possible compensatory UGT isoforms, we first verified that UGT1A activities were significantly lower (p Ͻ 0.05) in Gunn rats by using UGT1A-specific probes 7-ethyl-10-hydroxycamptothecin (SN-38) and prunetin. We then demonstrated using UGT2B probes testosterone, ezetimibe, and indomethacin that UGT2B activities were usually significantly higher in Gunn rats. In addition, testosterone was metabolized much faster in liver microsomes than in intestinal microsomes, and in microsomes prepared from Gunn rats compared with Wistar rats. In conclusion, flavonoids are efficiently metabolized by UGT1A-deficient Gunn rats because of compensatory up-regulation of intestinal UGT2Bs and hepatic anion efflux transporters, which increases their disposition and limits their oral bioavailabilities.

show abstract

Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity

Cited by 58 publications

References 30 publications

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

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

Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein

Disposition of Flavonoids via Enteric Recycling: UDP-Glucuronosyltransferase (UGT) 1As Deficiency in Gunn Rats Is Compensated by Increases in UGT2Bs Activities

Contact Info

Product

Resources

About