This study aimed to determine the reaction kinetics of the regioselective glucuronidation of diosmetin and chrysoeriol, two important methylated metabolites of luteolin, by human liver microsomes (HLMs) and uridine-5'-diphosphate glucuronosyltransferase (UGTs) enzymes. This study also investigated the effects of breast cancer resistance protein (BCRP) on the efflux of diosmetin and chrysoeriol ...

Esculetin (6,7-dihydroxycoumarin) and its C-4 derivatives have multiple pharmacologic activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Glucuronidation plays important roles in catechols elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of the human...

Kampo is a traditional Japanese herbal medicine and widely used in clinical practice in Japan. Little is known about interactions between Kampo and other medicines. Kampo contains many aglycones, which can be conjugated by UDP-glucuronosyltransferase (UGT). Therefore, in the present study, the effects of Kampo on human UGT1A1 activity were investigated in vitro. Substrates of human UGT1A1, beta...

The phase I cytochrome P450 (CYP) isoenzymes have received substantial attention in the pharmacogenetic literature. Researchers are beginning to examine the role of the phase II UDP-glucuronosyltransferase (UGT) enzymes, which produce products that are more water-soluble, less toxic and more readily excreted than the parent compounds. Several reasons may have contributed to neglect of UGTs (com...

Like other basic amphiphilic drugs, the (S)-enantiomer of the antiallergic drug ketotifen exhibited biphasic kinetics when it was converted to two isomeric quaternary ammonium-linked glucuronides in human liver microsomes. For (R)-ketotifen this applied when incubations were carried out in the absence of a detergent. Two UDP-glucuronosyltransferases (UGTs) present in human liver, UGT1A4 and UGT...

The usefulness of epirubicin in the treatment of adult and childhood malignant diseases is related in part to the potential reduction in cardiac toxicity compared with that of other anthracyclines given at equivalent doses. An important pathway for epirubicin detoxification is UGT2B7-dependent glucuronidation. This study was implemented to provide a preclinical evaluation of the metabolism of e...

The stilbenic compound (Z)-combretastatin A-4 (CA-4) has been described as a potent tubulin polymerization inhibitor. In vivo, CA-4 binds to tubulin and inhibits microtubule depolymerization, which results in morphological changes in proliferating endothelial cells. Combretastatin A-4 prodrug phosphate is a leading vascular disrupting agent and is currently being evaluated in multiple clinical ...

UDP-glucuronosyltransferase (UGT) activity toward the flavonoid quercetin and UGT protein were characterized in three equidistant small intestine (SI) segments from 4-, 12-, 18-, and 28-month-old male Fischer 344 rats (n = 8/age) using villin to control for enterocyte content. SI microsomal intrinsic clearance of quercetin was increased 3- to 9-fold from 4 months in the proximal and distal SI a...

Morphine is an important drug used to alleviate moderate to severe pain. This opiate is mainly metabolized by glucuronidation to a non-analgesic metabolite, morphine-3-glucuronide (M-3-G) and an active metabolite morphine-6-glucuronide (M-6-G). To understand the modulation of morphine glucuronidation activity by environmental factors, the effect of endogenous and food-derived compounds on morph...

Bilirubin, an end product of heme catabolism, is primarily eliminated via glucuronic acid conjugation by UGT1A1. Impaired bilirubin conjugation, caused by inhibition of UGT1A1, can result in clinical consequences, including jaundice and kernicterus. Thus, evaluation of the ability of new drug candidates to inhibit UGT1A1catalyzed bilirubin glucuronidation in vitro has become common practice. Ho...