Evaluation of hepatic clearance and drug-drug interactions of luteolin and apigenin by using primary cultured rat hepatocytes.

The hepatic clearance and drug-drug interactions of luteolin and apigenin were studied by using primary cultured rat hepatocytes. Luteolin and apigenin experienced extensive first-pass metabolism. The elimination percent of luteolin and apigenin was found to be 91.9% and 86.7% after 120 min of incubation. The predicted % liver blood flow was 82.3% and 85.4% for luteolin and apigenin, respectively. Total glucuronidated/sulfated conjugates of luteolin/apigenin were determined by an enzyme hydrolysis method. Compared with the elimination of pure luteolin and apigenin, the elimination of luteolin and apigenin was much lower in hydrolyzed Flos Chrysanthemi extract (FCE) containing comparable amounts of luteolin and apigenin. The effect of a series of flavonoids, including flavonols, flavones, isoflavone, flavanone, flavanonols and catechins, on the elimination of luteolin and apigenin was studied. At least four key determinants in the chemical structures of flavonoids are necessary for exerting the inhibitory effects on the conjugation: 1) catechol structure (3',4'-dihydroxylation) in the B-ring; 2) B-ring is attached to the C-2 position on the C-ring; 3) the C2-3 double bond in conjunction with the C4 carbonyl group on the C-ring; 4) no glycoside present. Investigation of clearance and interaction among flavonoids could help us better understand their bioavailability and offer insight into the approaches to be taken to minimize competitive effects, and to design appropriate bioavailability studies in humans.

Relative contribution of small and large intestine to deglycosylation and absorption of flavonoids from Chrysanthemun morifolium extract.

The flower of Chrysanthemum morifolium Ramat (CM) is an established part of traditional Chinese medicine (TCM). Luteolin and apigenin flavonoids are the effective components of the CM extract (CME); however, they exist in the orally consumed CME as glycosides. The present study was carried out to determine the relative contribution of the small and large intestine to the deglycosylation and absorption of flavonoids from CME using a rat model system. The distribution of luteolin and apigenin in rat gastrointestinal (GI) luminal contents, tissues, and plasmas was assessed after the oral administration of CME. The hydrolysis and absorption of CME flavonoids in different rat GI segments were further evaluated by using in situ ligated models and cell-free extracts prepared from rat GI segments. The results demonstrated that after the oral administration of CME, the magnitude of deglycosylation in rats was surprisingly high (about 30%) in the stomach and upper intestine within the first 5 min after ingestion, and early absorption in the plasma was detected. The results from site-limited administration revealed that the stomach was the initial hydrolysis site, while the duodenum was the first effective absorption site for CME flavonoids. Diminishing microbial flora in the jejunum had no significant effect on the hydrolysis of the flavonoids from CME, but the cell-free extracts prepared from rat GI segments demonstrated a strong ability to hydrolyze. Taken together, our findings suggest that enteric disposition contributes to the pharmacokinetics of luteolin and apigenin after oral administration of CME. Moreover, the upper digestive tract plays a key role in the hydrolysis and absorption of flavonoids in CME.