Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.
"Generally, flavonoid compounds exhibit very low bioavailability due to extensive first-pass metabolisms, in particular, intestinal and hepatic glucuronidation  . Recently, the reports demonstrating that glucuronidated metabolites of some flavonoid compounds, such as quercetin, genistein, and daidzein, were equally or even more pharmacologically active than the parent compounds    have boosted research interests on pharmacological evaluation of the phase II conjugates of the flavonoids. In the past two decades, the structure-glucuronidation relationship (SGR) of flavonoids has been extensively reported , which provides important information for biosynthesis of flavonoid glucuronides with desired biological activities for pharmaceutical purposes as well as prediction of drug interactions. "
[Show abstract][Hide abstract] ABSTRACT: Hepatic conjugation plays important roles in systemic exposure and drug interactions of flavonoids. In the present study, the hepatic metabolism of calycosin, a major isoflavone from Astragali Radix, was characterized and the regioselectivity in the predominant glucuronidation pathway was first delineated in human liver microsomes (HLMs) and a panel of recombinant human UDP-glucuronosyltransferases (UGTs). Calycosin underwent major glucuronidation and minor oxidation and sulfation in human liver subcellular fractions. The major glucuronide (G2) of calycosin was isolated and identified as calycosin 3'-glucuronide by NMR analysis, and thus, the minor glucuronide (G1) was tentatively assigned as calycosin 7-glucuronide. The formations of both glucuronides in HLMs fit typical Michaelis-Menten kinetics. HLMs exhibited higher affinity (Km, G2 12.37 ± 1.20 μM vs G1 40.90 ± 5.51 μM) and velocity (Vmax, G2 5.39 ± 0.13 nmol/min/mg protein vs G1 2.80 ± 0.13 nmol/min/mg protein) on G2 formation, leading to the intrinsic clearance of calycosin via 3'-glucuronidation 6 times that through 7-glucuronidation. UGT1A1, 1A3 and 1A10 showed activities on both 3'-OH and 7-OH, whereas UGT1A7, 1A8, 1A9, and 2B7 were only capable of catalyzing 3'-OH glucuronidation of calycosin. Among them, UGT1A9 exhibited the highest activity (Clint, 2169.50 μL/min/mg protein) for 3'-glucuronide formation followed by UGT1A7 (Clint, 396.38 μL/min/mg protein). UGT1A1 showed the highest activity towards 7-OH glucuronidation (Clint, 224.34 μL/min/mg protein), which was comparable to its activity on 3'-OH glucuronidation (Clint, 203.82 μL/min/mg protein). Propofol (UGT1A9 inhibitor) produced a complete inhibition of 3'-glucuronide formation accompanied by an increase of 7-glucuronide in HLMs, while bilirubin (UGT1A1 inhibitor) only partially (∼60%) inhibited the 7-OH glucuronidation. These findings demonstrated the regioselective glucuronidation at the 3'-OH of the isoflavone calycosin in HLMs and shed light on potential drug interactions of calycosin with other UGT1A9 substrates.
"Ezetimibe is indicated as an adjunctive therapy to diet for the reduction of hypercholesterolemia. Ezetimibe localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite) (Table 1)       by glucuronosyltransferase. Ezetimibe glucuronide shows higher activity in inhibiting cholesterol absorption than ezetimibe itself. Mean c max (45—71 ng/ml) "
[Show abstract][Hide abstract] ABSTRACT: Authorities of Drug Administration in the United States of America approved about 5000 drugs for use in the therapy or management of several diseases. About two hundred of these drugs have active metabolites and the knowledge of their medicinal chemistry is important both in medical practice and pharmaceutical research. This review gives a detailed description of the medicinal chemistry of drugs with active metabolites generated after conjugation. This review focused on glucuronide-, acetyl-, sulphate- and phosphate-conjugation of drugs, converting the drug into an active metabolite. This conversion essentially changed the lipophilicity of the drug.
Mini Reviews in Medicinal Chemistry 10/2013; 13(11):1550-63. · 2.90 Impact Factor
"Ezetimibe was discovered as an active and potent metabolite of Schering-Plough's SCH48461 substance and introduced as the first of a new class of selective cholesterol absorption inhibitor. Ezetimibe is absorbed and metabolized by intestine and liver to its glucuronide . Both ezetimibe and its metabolite inhibit intestinal cholesterol absorption by preventing cholesterol transport from intestinal lumen to small intestinal enterocytes , resulting in lowering plasma cholesterol by 15% to 20% . "
[Show abstract][Hide abstract] ABSTRACT: Polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1) is localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It mediates intestinal cholesterol absorption and prevents extensive loss of cholesterol by transporting biliary cholesterol into hepatocytes. NPC1L1 is a molecular target of ezetimibe, an agent for hypercholesterolemia. Recently, NPC1L1 inhibition has been shown to prevent metabolic disorders such as fatty liver disease, obesity, diabetes, and atherosclerosis. In this review, the identification and characterization of NPC1L1, NPC1L1-dependent cholesterol transport, the relationship with pathogenesis of metabolic disease and its newly introduced function for virus entry are discussed.
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