Pharmacokinetic Study of Nobiletin and Tangeretin in Rat Serum by High-Performance Liquid Chromatography−Electrospray Ionization−Mass Spectrometry

Abstract

Nobiletin (NOB) and tangeretin (TAN), two of the main polymethoxylated flavones (PMFs) in citrus, influence a number of key biological pathways in mammalian cells. Although the impacts of NOB and TAN on glucose homeostasis and cholesterol regulation have been investigated in human clinical trials, much information is still lacking about the metabolism and oral bioavailability of these compounds in animals. In this study, NOB and TAN were administered to rats by gavage and intraperitoneal (ip) injection, and the blood serum concentrations of these compounds and their main metabolites were monitored by high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS). In addition to the administered compounds, two metabolites of TAN and eight metabolites of NOB were detected and measured over 24 h. With identical oral doses, nearly 10-fold higher absorption of NOB occurred compared to TAN. For both compounds, maximum levels of glucuronidated metabolites occurred in the blood serum at later time points (∼5-8 h) compared to the earlier T(max) values for NOB and TAN. In most cases the glucuronides occurred at substantially higher concentrations than the aglycone metabolites. Low levels of NOB and TAN and their metabolites were detectable in rat blood serum even at 24 h after treatment.

Bioavailability of Citrus Polymethoxylated Flavones and Their Biological Role in Metabolic Syndrome and Hyperlipidemia

“…Results from this study demonstrated that with identical oral doses nearly 10-fold higher absorption of nobiletin occurred in comparison to tangeretin. Further, in the blood serum, maximum levels of glucuronidated metabolites occurred later than nobiletin and tangeretin and occurred at higher concentrations than aglycone metabolites (Manthey et al, 2011). It is also confirmed in previous trials that overall expression of biological actions of nobiletin and tangeretin in animals is due to the biological actions of aglycone metabolites (Eguchi et al, 2007;Li et al, 2007;Lai et al, 2008;Xiao et al, 2009).…”

“…In a recent study by Manthey et al, 2011, nobiletin and tangeretin were administered to rats by gavage and intraperitoneal (ip) injection. By using high-performance liquid chromatography−electrospray ionization−mass spectrometry (HPLC-ESI-MS), blood serum concentrations of metabolites were monitored.…”

Determination of Nobiletin in Rat Plasma after Ingestion of <i>Citrus depressa</i> Juice by Capillary Liquid Chromatography with Electrochemical Detection Using Boron-doped Diamond Electrode

“…And, the bioavailability of tangeretin was remarkably lower than that of nobiletin at a relatively high dosage of tangeretin and nobiletin standard. 9 Thus, the concentration of tangeretin in the present study is expected to be lower than 3 ng mL…”

“…4 In addition, nobiletin has been found to exert antitumor activities, 5,6 to inhibit fulminant hepatitis, 7 and to improve memory impairment. 8 Although pharmacokinetic studies of nobiletin have been performed to examine the further characterizations of the metabolism and the biological effects of nobiletin, it have been carried out at relatively high dosage of nobiletin [9][10][11] since a sensitive analytical method has not been available. In order to discuss the realistic effects of nobiletin which, for example, are observed after daily beverage ingestion, an analytical method with high sensitivity is necessary for determining nobiletin in plasma.…”

Cellular Antioxidant Activity and Pharmacokinetic Study of Polymethoxylated Flavonoids in Extract of Citrus reticulata ‘Chachi’ Peel

“…It is of great importance to obtain the detailed pharmacokinetics and to find out the relationship between oral dosage and antioxidant effect of ECRP PMFs. Although Manthey et al (2011) andSaigusa et al (2011) have developed simultaneous determination methods to measure the contents of PMFs in sera of animals, they just focused on the pharmacokinetics of purified compounds. In contrast, the pharmacokinetics and bioavailability of PMFs in plant extract have never been reported hitherto.…”