The regioselectivity of phase II conjugation of flavonoids is expected to be of importance for their biological activity. In the present study, the regioselectivity of phase II biotransformation of the model flavonoids luteolin and quercetin by UDP-glucuronosyltransferases was investigated. Identification of the metabolites formed in microsomal incubations with luteolin or quercetin was done using HPLC, LC-MS, and (1)H NMR. The results obtained demonstrate the major sites for glucuronidation to be the 7-, 3-, 3'-, or 4'-hydroxyl moiety. Using these unequivocal identifications, the regioselectivity of the glucuronidation of luteolin and quercetin by microsomal samples from different origin, i.e., rat and human intestine and liver, as well as by various individual human UDP-glucuronosyltransferase isoenzymes was characterized. The results obtained reveal that regioselectivity is dependent on the model flavonoid of interest, glucuronidation of luteolin and quercetin not following the same pattern, depending on the isoenzyme of UDP-glucuronosyltransferases (UGT) involved. Human UGT1A1, UGT1A8, and UGT1A9 were shown to be especially active in conjugation of both flavonoids, whereas UGT1A4 and UGT1A10 and the isoenzymes from the UGTB family, UGT2B7 and UGT2B15, were less efficient. Due to the different regioselectivity and activity displayed by the various UDP-glucuronosyltransferases, regioselectivity and rate of flavonoid conjugation varies with species and organ. Qualitative comparison of the regioselectivities of glucuronidation obtained with human intestine and liver microsomes to those obtained with human UGT isoenzymes indicates that, in human liver, especially UGT1A9 and, in intestine, UGT1A1 and UGT1A8 are involved in glucuronidation of quercetin and luteolin. Taking into account the fact that the anti-oxidant action as well as the pro-oxidant toxicity of these catechol-type flavonoids is especially related to their 3',4'-dihydroxyl moiety, it is of interest to note that the human intestine UGT's appear to be especially effective in conjugating this 3',4' catechol unit. This would imply that upon glucuronidation along the transport across the intestinal border, the flavonoids loose a significant part of these biological activities.

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Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of >500 ng/ml and <2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n ‫؍‬ 20) and 300 mg posaconazole once daily (n ‫؍‬ 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for <28 days. The current commercial formulation, posaconazole oral suspension, has been effective and generally well tolerated as IFI prophylaxis when given to neutropenic patients after chemotherapy for AML or MDS. Previously, in a large, global, phase 3 controlled clinical trial of such patients, treatment with 200 mg posaconazole oral suspension three times daily resulted in fewer proven or probable IFIs (2% versus 8%; P Ͻ 0.001), lower incidences of invasive aspergillosis (1% versus 7%; P Ͻ 0.001), and prolonged survival (P ϭ 0.04) than treatment with itraconazole or fluconazole (1). In a similar controlled study in immunosuppressed patients with graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation, compared with fluconazole, posaconazole oral suspension effectively prevented invasive mold infections and reduced the related mortality rate (2).Despite its effectiveness in the registration trials, the posaconazole oral suspension has practical limitations: it must be administered multiple times daily and must be taken with food (high-fat diet preferred) so that adequate systemic exposure can be achieved (3, 4). These limitations are particularly important in hematology patients eligible for antifungal prophylaxis, in whom chemotherapy-induced adverse effects, including severe nausea or vomiting, mucositis, and diarrhea, often make it difficult to ensure adequate food intake to optimize exposure of the posaconazole oral suspension (5-7). Until now, absorption could be enhanced in these patients if posaconazole doses were divided (200 mg four times daily) or if the drug was administered with a liquid nutritional supplement or an acidic drink such as ginger ale (4,8). Even with these measures, target exposures in many patients could not be achieved; 25% of patients with neutropenia achieved steady-state plasma concentrations of Ͻ322 ng/ml when taking the recommended 200-mg dose of the posaconazole oral suspension three times a day for antifungal ...

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