Determination of rat oral bioavailability of soy-derived phytoestrogens using an automated on-column extraction procedure and electrospray tandem mass spectrometry

Mallis, Larry M.; Sarkahian, Ani; Harris, Heather A.; Zhang, Meiyi; McConnell, Oliver J.

doi:10.1016/j.jchromb.2003.08.003

Cited by 58 publications

(46 citation statements)

References 72 publications

(71 reference statements)

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“…Although BCA has poor bioavailability, enterohepatic recycling may provide a longer period of exposure. Additionally, comparison of our study results with those of Mallis et al 42 suggests the possibility that bioavailability may be improved if combinations of fl avonoids are administered. BCA and its metabolite GEN are widely ingested as isofl avone herbal preparations and are being investigated for their cardiovascular and chemopreventive effects, as well as in the treatment of menopausal symptoms.…”

Section: E441supporting

confidence: 72%

“…In a previous study in rats in which BCA was administered as 1 component of a mixture of 5 fl avonoids, including the isofl avones daidzein and GEN, its oral bioavailability was reported to be 21.3%. 42 The higher bioavailability in this study compared with the current investigation may be due to 2 factors. First, 5 compounds (including isofl avones, daidzein, and GEN) were administered simultaneously 42 ; these other isofl avones, …”

Section: Discussionmentioning

confidence: 53%

“…42 The higher bioavailability in this study compared with the current investigation may be due to 2 factors. First, 5 compounds (including isofl avones, daidzein, and GEN) were administered simultaneously 42 ; these other isofl avones, …”

Section: Discussionmentioning

confidence: 53%

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Pharmacokinetics and bioavailability of the isoflavone biochanin A in rats

Moon

Sagawa

Frederick

et al. 2006

AAPS J

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Biochanin A (BCA) is a dietary isofl avone present in legumes, most notably red clover, and in many herbal dietary supplements. BCA has been reported to have chemopreventive properties and is metabolized to the isofl avone genistein (GEN), BCA conjugates, and GEN conjugates. The metabolites may contribute to the chemopreventive effects of BCA. The absorption, metabolism, and disposition of BCA have not been determined in rats. Our objective was to evaluate the pharmacokinetics and metabolism of BCA in rats. Male Sprague-Dawley rats were administered BCA by intravenous injection (1 and 5 mg/kg), by intraperitoneal injection (5 and 50 mg/kg), and orally (5 and 50 mg/kg). Plasma and bile samples were enzymatically hydrolyzed in vitro to determine conjugate concentrations for BCA and GEN. Equilibrium dialysis was used to determine protein binding. The BCA and GEN concentrations in plasma, urine, and bile were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The pharmacokinetic parameters of BCA were analyzed by noncompartmental analysis. Signifi cant levels of BCA conjugates and GEN conjugates were detected in plasma and bile. Both BCA and GEN were found to have a high clearance and a large apparent volume of distribution; the bioavailability of both was poor (<4%). Reentry peaks were evident after oral administration of both BCA and GEN, suggesting enterohepatic cycling. The free fraction of BCA in rat plasma was 1.5%. A 2-compartment model that included both linear and nonlinear clearance terms and enterohepatic recirculation best described the plasma data. This represents the fi rst evaluation of the dose-dependent pharmacokinetics and metabolism of BCA in rats.

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Section: E441supporting

confidence: 72%

Section: Discussionmentioning

confidence: 53%

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Pharmacokinetics and bioavailability of the isoflavone biochanin A in rats

Moon

Sagawa

Frederick

et al. 2006

AAPS J

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“…Assuming a bioavailability of 10%, which was reported after oral application of isoflavones to rats (Mallis et al 2003), we chose two doses of 8PN to study the effects in the hypothalamo-pituitary-uterine axis and to compare them with a low and high dose of E2. E2 was administered as 17 -estradiol-3-benzoate (E2B) to improve the low oral bioavailability of E2 (Schleicher et al 1998), and doses were chosen according to experience and standard protocol in the laboratory (Seidlova-Wuttke et al 2003b, 2004a.…”

Section: Introductionmentioning

confidence: 99%

Effects of 8-prenylnaringenin on the hypothalamo-pituitary-uterine axis in rats after 3-month treatment

Christoffel¹,

Rimoldi²,

Wuttke³

2006

Journal of Endocrinology

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Phytoestrogens are increasingly consumed in artificially high doses as herbal preparations and nutritional supplements. The flavanone 8-prenylnaringenin (8PN) is a potent phytoestrogen, but its benefits and risks after long-term application are poorly identified. Therefore, we tested two doses of 8PN and 17 -estradiol-3-benzoate (E2B) (effective doses: 6·8 and 68·4 mg/kg body weight (BW) of 8PN, and 0·17 and 0·7 mg/kg BW of 17 -estradiol (E2)) and compared their effects on uterine weight, pituitary hormones (LH, FSH and prolactin) and the expression of estrogen-regulated genes and of estrogen receptor (ER) and ER in the hypothalamus, pituitary and uterus. Both doses of E2 and the high dose of 8PN suppressed serum LH and FSH, and stimulated serum prolactin levels, uterine weight, and progesterone receptor, insulin-like growth factor I and complement protein C3 mRNA transcripts. In the preoptic and the mediobasal areas of the hypothalamus, all treatments had negligible effects on ER and ER and gonadotropin-releasing hormone (GnRH) receptor gene expression, while ER and GnRH receptor transcripts in the anterior pituitary were reduced under both E2 doses and the high 8PN dose. The mRNA concentrations of the LH andsubunits in the pituitary were suppressed by E2 and 8PN. In summary, 8PN had very similar though milder effects than E2 on all tested parameters. Inhibition of climacteric complaints by E2 takes place in the hypothalamus, where it inhibits the overactive GnRH pulse generator. Hence, 8PN may be used to inhibit climacteric symptoms effectively. Human pharmacologic studies will show whether the stimulatory effect on the uterus that was found in the present animal model would require the concomitant administration of progestins to prevent endometrial overstimulation.

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“…A search in the literature shows that bioavailability data in rats are only available for genistein (Coldham et al, 2002;Mallis et al, 2003), daidzein (Lamartiniere et al, 2002;Mallis et al, 2003), and biochanin A (Mallis et al, 2003). With respect to our microsome-derived kinetic parameters, no correlation can be made with the bioavailability data from these in vivo studies.…”

Section: Structural Effects On Intestinal Disposition Of Isoflavonesmentioning

confidence: 99%

Disposition of Flavonoids via Enteric Recycling: Structural Effects and Lack of Correlations between in Vitro and in Situ Metabolic Properties

Wang¹,

Chen²,

Jia³

et al. 2006

Drug Metabolism and Disposition

111

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ABSTRACT:The purpose of this study is to determine the importance of coupling of efflux transporters and metabolic enzymes in the intestinal disposition of six isoflavones (genistein, daidzein, formononetin, glycitein, biochanin A, and prunetin), and to determine how isoflavone structural differences affect the intestinal disposition. A rat intestinal perfusion model was used, together with rat intestinal and liver microsomes. In the intestinal perfusion model, significant absorption and excretion differences were found between isoflavones and their respective glucuronides (p <0.05), with prunetin being the most rapidly absorbed and formononetin glucuronides being the most excreted in the small intestine. In contrast, glucuronides were excreted very little in the colon. In an attempt to account for the differences, we measured the glucuronidation rates of six isoflavones in microsomes prepared from rat intestine and liver. Using multiple regression analysis, intrinsic clearance (CL int ) and other enzyme kinetic parameters (V max and K m ) were determined using appropriate kinetic models based on Akaike's information criterion. The kinetic parameters were dependent on the isoflavone used and the types of microsomes. To determine how metabolite excretion rates are controlled, we plotted excretion rates versus calculated microsomal rates (at 10 M), CL int values, K m values, or V max values, and the results indicated that excretion rates were not controlled by any of the kinetic parameters. In conclusion, coupling of intestinal metabolic enzymes and efflux transporters affects the intestinal disposition of isoflavones, and structural differences of isoflavones, such as having methoxyl groups, significantly influenced their intestinal disposition.

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Determination of rat oral bioavailability of soy-derived phytoestrogens using an automated on-column extraction procedure and electrospray tandem mass spectrometry

Cited by 58 publications

References 72 publications

Pharmacokinetics and bioavailability of the isoflavone biochanin A in rats

Pharmacokinetics and bioavailability of the isoflavone biochanin A in rats

Effects of 8-prenylnaringenin on the hypothalamo-pituitary-uterine axis in rats after 3-month treatment

Disposition of Flavonoids via Enteric Recycling: Structural Effects and Lack of Correlations between in Vitro and in Situ Metabolic Properties

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