The development of general pharmacokinetic model for combined quercetin and metabolites: A low bioavailable compound with high bioavailable metabolites.

摘要

Quercetin (3,5,7,3′,4′-pentahydroxyflavanone) is a putative active compound which is widely distributed in many dietary and medicinal plants including vegetables, onion, apple, tea, ginkgo biloba, allium cepa, solanum lycopersicum, and others.; To verify and understand the poor absorption or bioavailability of unchanged quercetin, the present study proposes to clarify various factors associated with unchanged quercetin absorption in vivo: (1) first pass in the gut, liver, and lung; (2) re-absorption; and (3) elimination in rats. Based on these results, a mathematical model to describe the pharmacokinetics (i.e. concentration time curve of unchanged quercetin following oral administration) will be constructed.; Quercetin was dissolved in hydroxypropyl-beta-cyclodextrin solution (about 4mg/ml) and then administered to rats by gastric gavage or intra-vascularly at a dose of 10mg/kg. The plasma concentrations of unchanged quercetin and total quercetin (unchanged quercetin + glucuronides/sulfates of quercetin) in rats were determined by HPLC. The bioavailabilities of unchanged quercetin and total quercetin were obtained by comparing the AUC in systemic circulation after oral and iv administration. Excretions from urine and feces were determined after iv administration. In addition, the elimination from bile was investigated in bile duct cannulated rats following iv administration of quercetin. The rate and extent of absorption was evaluated by comparing the AUC in portal vein plasma and in systemic circulation after oral administration. The “gut effect” was evaluated by comparing the differences in AUC after oral, intraportal, and iv administration.; The results showed that only 3.5% of unchanged quercetin was available in the systemic circulation although the total absorbed quercetin (unchanged quercetin plus conjugated metabolites absorbed) was as high as 59.1%. Following oral administration, 93.3% of oral quercetin was practically metabolized in the gut lumen and gut wall. Only about 3.1% of oral dose was actually metabolized in the liver. Pulmonary first-pass effect did not play an important role in the glucuronidation/sulfation of unchanged quercetin. Conjugated quercetins were mostly excreted into the bile and then into the duodenum, only trace amount of the conjugates of quercetin were reabsorbed. Unchanged quercetin was not found in bile. Less than 1% of dose was excreted in the urine and feces as unchanged quercetin. (Abstract shortened by UMI.)