Indometacin undergoes hepatic metabolism involving glucuronidation, O-desmethylation, and N-deacylation. O-desmethyl-indomethacin, N-deschlorobenzoyl-indomethacin, and O-desmethyl-N-deschlorobenzoyl-indomethacin metabolites and their glucuronides are primarily inactive and have no pharmacological activity. Unconjugated metabolites are also detected in the plasma. Its high bioavailability indicates that indometacin is unlikely to be subject to the first-pass metabolism.
Indomethacin is metabolized in the liver to its glucuronide conjugate and to desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites and their glucuronides. These metabolites do not appear to possess anti-inflammatory activity. A portion of the drug is also N-deacylated by a nonmicrosomal system.
Indomethacin has known human metabolites that include (2S,3S,4S,5R)-6-[2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetyl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid and O-Desmethylindomethacin.
来源:NORMAN Suspect List Exchange
代谢
肝脏。
消除途径：吲哚美辛通过肾脏排泄、代谢和胆汁排泄消除。
半衰期：4.5小时
Hepatic.
Route of Elimination: Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Half Life: 4.5 hours
IDENTIFICATION AND USE: Indomethacin is a pale-yellow to yellow-tan, crystalline powder. It is an anti-inflammatory drug. It is also indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management is ineffective. HUMAN EXPOSURE AND TOXICITY: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events. NSAIDs may also cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIDs. Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving indomethacin. Drowsiness, lethargy, mental confusion, nausea, vomiting, paresthesia, numbness, aggressive behavior, disorientation, and seizures have been reported following acute overdosage of the drug. Exposure of the fetus to indomethacin by administration of the drug to the mother may cause many side effects, including premature closure of the ductus arteriosus. Short-term indomethacin administered within 4 days prior to delivery resulted in a transient, yet significant renal dysfunction. ANIMAL STUDIES: Acute oral administration of indomethacin to rats induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. After subchronic exposure to indomethacin for six to 12 weeks, rats displayed microcytic anemia, hypoalbuminemia, small intestinal ulceration, cecal ulceration and inconspicuous raised mucosal lesions in the cecum that histologically showed submucosal fibrosis with disruption and thickening of the apical muscularis mucosa. Indomethacin had no effect on fertility in rats or mice at dosages up to 0.5 mg/kg daily. In rats and mice, 4 mg/kg/day given during the last three days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. Teratogenic studies were conducted in mice and rats at dosages of 0.5, 1, 2, and 4 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli with or without metabolic activation) and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethal mutations in Drosophila, and the micronucleus test in mice. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day.
Antiinflammatory effects of Indomethacin are believed to be due to inhibition of cylooxygenase in platelets which leads to the blockage of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Indomethacin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. Indomethacin is more selective for COX-1 than COX-2, which accounts for its increased adverse gastric effects relative to other NSAIDs. COX-1 is required for maintaining the protective gastric mucosal layer. The analgesic, antipyretic and anti-inflammatory effects of indomethacin occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.
Mild and transient elevations in serum aminotransferase levels are found in up to 15% of patients taking indomethacin chronically. Moderate ALT elevations (>3 times ULN) occur in less than 1% of patients. Frank liver injury with jaundice from indomethacin is rare (estimated at 1.1 per 100,000 prescriptions), and fewer than a dozen cases have been reported in the literature. The latency to onset of symptoms or jaundice is variable, but is usually within 1 to 8 weeks of starting, although instances of latency of 4 to 6 months have been reported. Patients present with anorexia, nausea and vomiting followed by jaundice. Hepatocellular patterns of enzyme elevations are most common, but cholestatic and mixed patterns have been reported. Allergic manifestations and autoimmune features are not common. The injury is usually self-limited, resolving in 1 to 3 months, but several fatal cases have been reported (Case 1), particularly after use of high doses in patients with juvenile rheumatoid arthritis or Still disease. Many of the reported cases of severe indomethacin associated hepatotoxicity have occurred in patients with a pre-existing, underlying chronic liver disease.
Indometacin displays a linear pharmacokinetics profile where the plasma concentrations and area under the curve (AUC) are dose-proportional, whereas half-life (T1/2) and plasma and renal clearance are dose-dependent. Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration and about 90% of the dose is absorbed within 4 hours. The bioavailability is about 80-90% following rectal administration. The peak plasma concentrations following a single oral dose were achieved between 0.9 ± 0.4 and 1.5 ± 0.8 hours in a fasting state. Despite large intersubject variation as well using the same preparation, peak plasma concentrations are dose-proportional and averaged 1.54 ± 0.76 μg/mL, 2.65 ± 1.03 μg/mL, and 4.92 ± 1.88 μg/mL following 25 mg, 50 mg, and 75 mg single doses in fasting subjects, respectively. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.
Indometacin is eliminated via renal excretion, metabolism, and biliary excretion. It is also subject to enter the enterohepatic circulation through excretion of its glucuronide metabolites into bile followed by resorption of indometacin after hydrolysis. The extent of involvement in the enterohepatic circulation ranges from 27 to 115%. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent in the feces (1.5 percent as indomethacin).
The volume of distribution ranged from 0.34 to 1.57 L/kg following oral, intravenous, or rectal administration of single and multiple doses of indometacin in healthy individuals. Indometacin is distributed into the synovial fluid and is extensively bound to tissues. It has been detected in human breast milk and placenta. Although indometacin has been shown to cross the blood-brain barrier (BBB), its extensive plasma protein binding allows only the small fraction of free or unbound indometacin to diffuse across the BBB.
来源:DrugBank
吸收、分配和排泄
清除
在临床药代动力学研究中，吲哚美辛的血浆清除率报告为口服给药后从1到2.5 mL/kg/min不等。
In a clinical pharmacokinetic study, the plasma clearance of indometacin was reported to range from 1 to 2.5 mL/kg/min following oral administration.
Patent ductus arteriosus (PDA) is a frequent complication in premature infants. Intravenous indomethacin is the standard mode of medical therapy and has been shown to be efficacious in closing the ductus. In our setup, oral indomethacin is being regularly used for medical treatment of suspected or clinically diagnosed PDA. Non-availability of the parenteral preparation and lack of information regarding the pharmacokinetic disposition of indomethacin in the premature infants in north Indian population led us to conduct this pharmacokinetic study with oral indomethacin. Twenty premature infants with gestational age 30.3 +/- 0.3 wk and birth weight, 1209.8 +/- 39.5 g; admitted to the neonatal unit of the Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh were enrolled in the study. Indomethacin was administered in a single oral dose of 0.2 mg/kg and blood samples were collected through an indwelling vascular catheter at 0 and 1, 2, 4, 8 and 12 hr after administration of indomethacin. Plasma indomethacin concentrations were assayed by spectrofluorometric technique. Large interindividual variability was observed for peak plasma concentrations (Cmax; 137.9 +/- 14.0 ng/mL), elimination half-life (t1/2 el; 21.4 +/- 1.7 hr) and area under the plasma concentrations time curve (AUC0-infinity;4172 +/- 303 ng.hr/mL) in these infants. Variables like birth weight, and sex did not have any sigiificant effect on indomethacin pharmacokinetics. However, the plasma t1/2 el of indomethacin was significantly (P < 0.01) larger in older infants (gestational age > 30 wk) in comparison to younger ones (gestational age < or = 30 wk). There was a negative correlation between gestational age and elimination t1/2 (r = -0.77). In conclusion, indomethacin pharmacokinetics showed a wide variability in premature infants. In view of these findings it can be suggested that infants of smaller gestational age are at greater risk of cumulative toxicity if more than one dose of indomethacin is given. With advancing age, metabolism as well as elimination of drug is faster that may require modification in indomethacin dose to achieve therapeutic response. These preliminary results may be of use in designing future pharmacokinetic studies of oral indomethacin in preterm neonates on a larger sample.
Non-estrogenic metabolites of diethylstilbestrol produced by prostaglandin synthase mediated metabolism
摘要：
Incubation of trans-diethylstilbestrol (E-DES) with prostaglandin synthase (PGS) in vitro leads to the formation of the metabolites cis, cis-dienestrol (Z,Z-DIES) and cis-diethylstilbestrol (Z-DES) which have considerably decreased estrogenic activity compared to their parent compound. Incubations of (14C)-E-DES with PGS in the presence of arachidonic acid (AA) predominantly catalyze formation of the oxidative metabolite Z,Z-DIES, accompanied by the formation of protein bound radioactivity. Inhibition of peroxidative metabolism through addition of indomethacin or absence of AA favors isomerization of E-DES to Z-DES without concomitant formation of protein bound radioactivity. Isomerization is inhibited by phenidone (1-phenyl-3-pyrazolidone). Since PGS activity is present in uterine tissue, these pathways may play a role in the metabolism of DES in its target tissue.
[EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
申请人：TAKEDA PHARMACEUTICAL
公开号：WO2010144486A1
公开（公告）日：2010-12-16
Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.
[EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
申请人：MERCK SHARP & DOHME
公开号：WO2015054038A1
公开（公告）日：2015-04-16
This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
申请人：Xu Feng
公开号：US20100120727A1
公开（公告）日：2010-05-13
In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
