concentration described by a two-compartment model (initial half-life of 8.8 minutes, terminal half-life of 2.4 hours). Because it undergoes rapid and extensive metabolism, the biological effects presumed from in vitro studies are unlikely to apply in vivo. Quercetin supplements in the aglycone form are less bioavailable than the quercetin glycoside often found in foods, especially red onions. Ingestion with high-fat foods may increase bioavailability compared to ingestion with low-fat foods, and carbohydrate-rich foods may increase absorption of quercetin by stimulating gastrointestinal motility and colonic fermentation. Metabolism Quercetin is rapidly metabolized (via glucuronidation) after the ingestion of quercetin foods or supplements. Five metabolites (quercetin glucuronides) have been found in human plasma after quercetin ingestion. Taken together, the quercetin glucuronides have a half life around 11-12 hours. In rats, quercetin did not undergo any significant phase I metabolism. In contrast, quercetin did undergo extensive phase II (conjugation) to produce metabolites that are more polar than the parent substance and hence are more rapidly excreted from the body. In vitro, the meta-hydroxyl group of catechol is methylated by catechol-O-methyltransferase. Four of the five hydroxyl groups of quercetin are glucuronidated by UDP-glucuronosyltransferase. The exception is the 5-hydroxyl group of the flavonoid ring which generally does not undergo glucuronidation. The major metabolites of orally absorbed quercetin are quercetin-3-glucuronide, 3'-methylquercetin-3-glucuronide, and quercetin-3'-sulfate. A methyl metabolite of quercetin has been shown in vitro to be more effective than quercetin at inhibiting lipopolysaccharide-activated macrophages. Compared to other flavonoids quercetin is one of the most effective inducers of the phase II detoxification enzymes. In-vitro studies show that quercetin is a strong inhibitor of the cytochrome P450 enzymes CYP3A4 and CYP2C19 and a moderate inhibitor of CYP2D6. Drugs that are metabolized by these pathways may have increased effect. An in-vivo study found that quercetin supplementation slows the metabolism of caffeine to a statistically significant extent in a particular genetic sub-population, but in absolute terms the effect was almost negligible. Pharmacological research Quercetin has been reported to inhibit the oxidation of other molecules and hence is classified as an antioxidant in vitro. It contains a polyphenolic chemical substructure that stops oxidation in vitro by acting as a scavenger of free radicals. Quercetin has been shown to inhibit the PI3K/AKT pathway leading to downregulation of the anti-apoptotic protein Bcl-w. Quercetin activates or inhibits the activities of a number of proteins in vitro. For example, it is a nonspecific protein kinase enzyme inhibitor.