PAMPA permeability, plasma protein binding, blood partition, pharmacokinetics and metabolism of formononetin, a methoxylated isoflavone

Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow-226001, Uttar Pradesh, India.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association (Impact Factor: 2.61). 05/2011; 49(5):1056-62. DOI: 10.1016/j.fct.2011.01.012
Source: PubMed

ABSTRACT Formononetin (FMN) is a methoxylated isoflavone which is the major constituent in red clover and in commercially available extracts of this plant. In this study, we investigated the parallel artificial membrane permeability assay (PAMPA) permeability, protein binding, blood uptake characteristics, pharmacokinetics and metabolism of FMN. The permeability study samples were analyzed by HPLC-PDA method; whereas the pharmacokinetic study, protein binding and whole blood partitioning samples were analyzed by LC-MS/MS method. The PAMPA permeability of FMN was found to be high at pH 4.0 and 7.0. Plasma protein binding of FMN was found to be 93.61±0.44% and 96.14±0.15% at the tested concentration of 50 and 150 ng/mL, respectively. FMN reached equilibrium fast between red blood cells (RBCs) and plasma, and the partition coefficients between RBCs and plasma (K(RBC/PL)) were independent of the initial rat blood concentrations of FMN. The bioavailability of unchanged/free FMN was found to be poor, i.e. approximately 3%. FMN was found to have a high clearance (5.13 L/h/kg) and a large apparent volume of distribution (14.16L/kg). Circulating conjugates (glucuronides/sulfates) of FMN and daidzein (DZN) were quantified using enzymatic hydrolysis of plasma samples. The levels of isoflavone glucuronides/sulfates were found to be much greater than that of the corresponding aglycones.


Available from: Muhammad Wahajuddin, Jun 02, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dietary isoflavones, popularly known as phytoestrogens, represent one of the most biologically active classes of flavonoids. Numerous in vitro and in vivo studies provide convincing evidence regarding their beneficial effects on human health. These isoflavones are increasingly being investigated as potential alternate therapies for a range of hormone-dependent conditions, including cancer, menopausal symptoms, osteoporosis and cardiovascular diseases. However, they exhibit poor oral bioavailability which limits their clinical utility in humans. The reason being, they are substrates of a plethora of enzymes and transporters and undergo extensive conjugative metabolism which facilitate their rapid elimination from biological systems. In addition, a number of experimental studies have also revealed that these isoflavones are potent inhibitors of various cytochrome P450 isoforms and transporters which play an important role in the disposition of many commonly prescribed drugs. Thus, there arise chances of observing clinically relevant herb-drug interactions which could sometimes be life-threatening. This review gives a comprehensive understanding of these dietary phytoestrogens with regard to their absorption, biodistribution and the role of enzyme-transporter interplay affecting their disposition in biological systems. Further, the effects of these phytoestrogens on the activity and kinetics of drug metabolizing enzymes and various clinically relevant influx/efflux transporters and the resulting diet-drug interactions have also been discussed.
    Current Drug Metabolism 01/2013; DOI:10.2174/1389200211314040002 · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aims of the present study were to study the interspecies difference in the pharmacokinetics of luteolin and apigenin occurring in Chrysanthemum morifolium extract (CME) among rats, beagle dogs, mini-pigs, and humans, and compared the human pharmacokinetic parameters with the data predicted from the above three animals. The plasma concentrations of luteolin and apigenin were determined with a RP-HPLC method. An interspecies difference of pharmacokinetics was found, especially between rats and other species, the plasma concentration of luteolin was much lower than that of apigenin in rats, although the content of luteolin in CME was higherthan that of apigenin, whereas the plasma concentration of luteolin was much higher than that of apigenin in dogs, mini-pigs and humans. Animal scale-up of some pharmacokinetic parameters of luteolin and apigenin were also performed after rats, beagle dogs, mini-pigs and humans were orally given CME at dosages of 400 mg/kg, 102 mg/kg, 90 mg/kg, and 20 mg/kg, respectively. Linear relationships were obtained between log mean retention time (MRT) and log species body weight (W) (kg), and log elimination half-life (t1/2) (h) and logW. The corresponding allometric equations were MRT=9.382W(0.1711) (R2 = 0.9999) and t1/2 = 4.811W(0.1093) (R2 = 0.9013) for luteolin, MRT = 12.53W(0.0356) (R2 = 0.9980) and t1/2 = 7.940W(0.0294) (R2 = 0.9258) for apigenin, respectively. The predicted human pharmacokinetic parameters (MRT and t1/2) by an allometric approach were 18.6 h and 7.46 h for luteolin, 14.3 h and 8.95 h for apigenin, respectively, which were close to the values obtained from humans (20 mg CME/kg) in the present study. The study has demonstrated the possibility to extrapolate the pharmacokinetic behavior of flavonoids from animals to humans.
    Pharmazie 03/2013; 68(3):195-200. DOI:10.1691/ph.2013.2744 · 1.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of seven bioactive components including paeoniflorin, nobiletin, tangeretin, liquiritigenin, isoliquiritigenin, liquiritin and formononetin in rat plasma and tissues after oral administration of Si-Ni-San extract using astragaloside IV as internal standard (IS). The plasma and tissue samples were extracted by solid-phase extraction. Chromatographic separation was accomplished on a C18 column with a multiple-step gradient elution. The quantification was obtained by scanning with multiple reaction monitoring via an electrospray ionization source that was operated by switching between the positive and negative modes in two MS/MS scan segments. Full validation of the assay was implemented. In conclusion, this method demonstrated good linearity and specificity. The lower limits of quantification for the analytes were <7.5 ng/mL. Intra- and inter-day precisions (RSD) were <12.5% and accuracy (RE) ranged from -10.2 to 7.3%. The average recoveries of the analytes from rat plasma and tissues were >65.2% and 58.6%, respectively. The validated method was further applied to the determination of actual rat plasma and tissues after oral administration of Si-Ni-San extract. The results provided a meaningful basis for the clinical application of this prescription. Copyright © 2013 John Wiley & Sons, Ltd.
    Biomedical Chromatography 04/2013; 27(8). DOI:10.1002/bmc.2904 · 1.66 Impact Factor