Studies Of Early Pharmacokinetic Of Nobiletin

Nobiletin (NOB) is a polymethoxyflavonoid (PMF) occurring exclusively in citrus fruits. Nobiletin are citrus flavonoids that are among the most effective at inhibiting cancer cell growth in vitro and in vivo. The purpose of this study was to explore the properties of absorption and metabolism and bioavailability of nobiletin.Solubility and LogD of asiaticoside were determined by Marvin Software. LogP and pK_a were predicted by computational method. The cytotoxic effect of compounds on Caco-2 cells and rat hepatocytes was assessed using the MTT or LDH test. Intestinal transport of compounds was measured using the single pass intestinal Perfusion technique in rats and MDCK cell monolayers. The metabolism of nobiletin was studied in vitro by incubation with rat and human liver microsomes, hepatocytes and enzymes of intestinal bacteria. Additionally, recovery of nobiletin from feces was quantified by performing in vivo experiments with the rat as animal model. HPLC and MS were employed to identify nobiletin and its metabolites.There are three indicators of nobiletin was in the range of 'rule of 5' . The computational method was able to predict LogP and LogD of nobiletin within logP 5. 5 units for the experimental data. To investigate the bioavailability of nobiletin in SD rats and Beagle dogs, The statistical moment was used to process concentration-time data. The Plasma bioavailability were 47.3% and 56.3% of nobiletin after orally administration in rats and dogs. Nobiletin were shown to be non-cytotoxic in Caco-2 cells, MDCK cells and rat hepatocytes. Passive, transcellular diffusion dominated the intestinal transport mechanism of nobiletin, with no evidence of p-glycoprotein involvement. Nobiletin was highly stable in rat liver microsomes and hepatocytes. Nobiletin was two metabolites in human liver microsomes. After oral administration , In the urinary samples, the main metabolites were deduced as 3' , 4'-dihydroxy-5, 6, 7, 8-tetramethoxyflavone(M1) , 4' -hydroxy-5 ,6 ,7 ,8 , 3' -Pentamethoxy-flavone (M2), 3' -hydroxy-5 ,6 ,7 ,8 ,4' -pentamethoxyflavone (M3).The primary methods of adsorption and metabolism in early phase of drug discovery were established. The Plasma bioavailability was 47. 3% and 56. 3% of nobiletin after orally administration in rats and dogs. The main best absorption in the jejunum. Nobiletin can be hydrolyzed by intestinal micro flora with the release of the corresponding aglycone. After oral administration, The Biotransformation study of nobiletin has shown that it undergoes demethylation pathway with the formation of mono-demethy-lated nobiletin as major metabolites.The method is simple, sensitiveness and the results provided reasonable evidence for the exploitation of nobiletion.