Allopurinol is rapidly metabolized to the corresponding xanthine analog, oxipurinol (alloxanthine), which is also an inhibitor of xanthine oxidase enzyme. Both allopurinol and oxypurinol inhibit the action of this enzyme. Allopurinol and oxypurinol are also converted by the purine salvage pathway to their respective ribonucleotides. The effect of these ribonucleotides related to the hypouricemic action of allopurinol in humans is not fully elucidated to this date. These metabolites may act to inhibit de novo purine biosynthesis by inhibiting the enzyme, _amidophosphoribosyltransferase_. The ribonucleotides have not been found to be incorporated in DNA.
Allopurinol and allopurinol sodium are rapidly metabolized by xanthine oxidase to oxypurinol, which is pharmacologically active. Rapid metabolism of allopurinol to oxypurinol does not seem to be affected substantially during multiple dosing. Pharmacokinetic parameters (eg, AUC, plasma elimination half-lives) of oxypurinol appear to be similar following oral administration of allopurinol and iv administration of allopurinol sodium.
来源:Hazardous Substances Data Bank (HSDB)
代谢
别嘌醇和氧嘌醇都是结合型，并形成它们各自对应的核糖核苷酸。
Both allopurinol and oxypurinol are conjugated and form their respective ribonucleosides.
Allopurinol-1-riboside, a major metabolite of allopurinol, is commonly thought to be directly synthesized by purine nucleoside phosphorylase (PNP) in vivo. As this enzyme is otherwise believed to function in vivo primarily in the direction of nucleoside breakdown, we have determined by high performance liquid chromatography and a conventional chromatographic method the urinary metabolites of allopurinol in a child deficient of PNP. In this patient approximately 40% of urinary allopurinol metabolites consisted of allopurinol-1-riboside, thus proving the possibility of indirect formation of allopurinol-1-riboside via allopurinol-1-ribotide in vivo, catalysed by hypoxanthine guanine phosphoribosyltransferase (HGPRT) and a phosphatase.
... The major and active metabolite, oxypurinol, is detected in the circulation within 15 minutes of allopurinol administration. Oxypurinol concentrations are higher than those of the parent drug and accumulation occurs during long term administration. ...Oxypurinol is eliminated by the kidney and has a much longer elimination half-life than allopurinol. Oxypurinol accumulates in patients with renal dysfunction; hence allopurinol dosages should be adjusted in such patients. ...
**Oral TDLO** (rat): 10 mg/kg; **Oral LD50** (mouse): 78 mg/kg; **Oral TDLO (mouse)**: 100 mg/kg **Use in pregnancy** Reproductive studies have been completed using rats and rabbit models at doses up to twenty times the normal human dose ( about 5 mg/kg per day), and it was concluded that fertility was not impaired and there was no fetal harm. There is a published report of a study in pregnant mice administered 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams administered 100 mg/kg allopurinol, however, death did not occur in those given 50 mg/kg. There were higher numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and higher numbers of skeletal malformations in fetuses at both doses on gestation day 13. Despite the above findings, there are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if it is absolutely required. **Use in nursing** Both allopurinol and the metabolite oxipurinol have been found in the milk of a mother who was receiving allopurinol. Since the effect of allopurinol on the nursing infant is unknown, it is advisable to exercise caution when allopurinol is taken by a nursing woman. **Mutagenicity and carcinogenicity** Cytogenic studies demonstrate that allopurinol does not induce chromosomal abnormalities in human blood cells in vitro at concentrations up to 100 g/mL and in vivo at doses up to 60 mg/day for an average duration of 40 months. Allopurinol does not form nitroso compounds (which may be carcinogenic) or affect lymphocyte transformation in vitro. Evidence suggests that allopurinol does not have deleterious effects on DNA at any stage of the cell cycle and was not found to be mutagenic. No evidence of carcinogenicity has been observed in mice treated with allopurinol for up to a 2 year period.
Chronic therapy with allopurinol is associated with transient and minor liver test abnormalities in 2% to 6% of patients, which resolve spontaneously or with drug discontinuation. More importantly, allopurinol has been linked to a very distinctive form of acute liver injury that is accompanied by prominent immunoallergic manifestations such as fever, rash, eosinophilia, lymphadenopathy, atypical lymphocytosis, thrombocytopenia, arthralgias and facial edema (drug reaction with eosinophilia and systemic symptoms — DRESS syndrome) (Case 1). The typical latency to onset is 2 to 8 weeks and liver injury arising during long term therapy is uncommon. The pattern of liver enzyme elevations tends to be mixed, but can be hepatocellular or purely cholestatic. Autoantibodies are not common. In some cases rash and fever arise before evidence of liver injury and rises in serum enzymes and bilirubin occur 1 to 2 weeks after the first immunoallergic manifestations. Eosinophilia in addition may arise only after the clinical manifestations. The systemic symptoms and signs of DRESS syndrome caused by allopurinol can also be manifested by renal, pulmonary or pancreatic dysfunction and even acalculous cholecystitis. More severe forms of allopurinol hypersensitivity reactions include Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), both of which are commonly accompanied by signs of liver injury, although the liver injury is often mild and transient serum aminotransferase elevations without jaundice. Overall, allopurinol hypersensitivity reactions have a high fatality rate, either from acute liver failure, chronic cholestatic injury or complications of other allergic manifestations such as toxic epidermal necrolysis, vasculitis, pancreatitis and renal dysfunction. African-American race and preexisting renal disease appear to be risk factors for hypersensitivity reactions to allopurinol.
Likelihood score: A (well established cause of clinically apparent liver injury).Histopathology
Liver biopsy in allopurinol hepatotoxicity typically shows an acute cholestatic or mixed hepatitis. Bile duct injury may be prominent early and loss of bile ducts later during the course. Histology can also show granulomas including "ring" granulomas that are typically associated with visceral infections such as Q fever or Kala-azar. Granulomas may be found in other organs as well and represent a typical histological correlate to the immunoallergic response to a medication. Two examples of allopurinol hepatotoxicity are shown: one with a cholestatic hepatitis and another with acute granulomatous changes.
CHOLESTATIC HEPATITISAllopurinol may cause cholestatic hepatitis. This case shows canalicular (arrow) and hepatocellular cholestasis in zone 3. Only very mild inflammation is present in this photo. The central vein (V) is indicated.In this case, there was mild portal inflammation, mainly composed of lymphocytes. In over half the portal areas, no duct could be found, consistent with a vanishing bile duct syndrome. This portal area only shows an artery (A) and vein (V).
GRANULOMATOUS HEPATITISThis case had granulomas in almost all of the portal areas. In this portal, the epithelioid macrophages (arrow) of the granulomas are in the center part of the portal area. The granuloma is surrounded by a mixed inflammatory infiltrate of lymphocytes, neutrophils and eosinophils. A cluster of eosinophils is indicated by the arrowhead.Another portal area showing a granuloma (arrow) along with mixed inflammation.A fibrin‐ring granuloma was present in this case. A fibrin‐ring granuloma is a granuloma that forms around a lipid droplet (L). A thin, irregular, ring of brightly eosinophilic fibrin can be seen running circumferentially around the lipid drop. It is best seen at the bottom (arrow).
This drug is about 90% absorbed from the gastrointestinal tract. Peak plasma levels normally occur at 1.5 hours and 4.5 hours post-dose for allopurinol and oxipurinol respectively. Following one oral dose of 300 mg of allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol were measured.
来源:DrugBank
吸收、分配和排泄
排除途径
大约80%口服摄入的别嘌醇以各种代谢物的形式在尿液中排出。大约20%摄入的别嘌醇通过粪便排出。
Approximately 80% of orally ingested allopurinol is found excreted in the urine as various metabolites. About 20% of ingested allopurinol is excreted in the feces.
Allopurinol and oxypurinol are both substrates for the enzyme xanthine oxidase, which is present in the cytoplasm of endothelial cells of capillaries, including sinusoids, with the highest activity demonstrated in the liver and intestinal lining. Tissue concentrations of allopurinol have not yet been reported in humans, however, it is probable that allopurinol and the metabolite oxypurinol would be measured in the highest concentrations in the abovementioned tissues. In animals, allopurinol concentrations are found to reach the highest levels in the blood, liver, intestine and heart, and lowest in the brain and lung tissues.
Since allopurinol and its metabolites are mainly eliminated by the kidney, accumulation of this drug can occur in patients with renal dysfunction or failure, and the dose of allopurinol should, therefore, be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of allopurinol is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not be higher than 100 mg. With severe renal impairment (creatinine clearance measured at less than 3 mL/min) a longer interval between doses may be required.
Following oral administration, approximately 80-90% of a dose of allopurinol is absorbed from the GI tract. Peak plasma concentrations of allopurinol are reached 2-6 hours after a usual dose.
The present invention provides compounds of Formula I,
1
including pharmaceutically acceptable salts and/or prodrugs thereof, where G, R
2
, and R
3
are defined as described herein.
本发明提供了公式I的化合物，包括其药学上可接受的盐和/或前药，其中G、R2和R3的定义如本文所述。
Organic semiconductor photocatalyst can bifunctionalize arenes and heteroarenes
作者：Indrajit Ghosh、Jagadish Khamrai、Aleksandr Savateev、Nikita Shlapakov、Markus Antonietti、Burkhard König
DOI：10.1126/science.aaw3254
日期：2019.7.26
Two-for-one approach to photoredox In photoredox catalysis, an excited chromophore typically activates a single reactant either by oxidizing or reducing it. Ghosh et al. used a semiconductor catalyst to activate two reactants at once by quenching both an excited electron and the residual positive hole (see the Perspective by Swift). As such, two different reactive carbon or halide fragments could be
光氧化还原二合一方法 在光氧化还原催化中，激发的发色团通常通过氧化或还原单个反应物来激活它。戈什等人。使用半导体催化剂通过淬灭激发的电子和残留的空穴来同时激活两种反应物（参见 Swift 的观点）。因此，可以将两个不同的反应性碳或卤化物片段附加到芳环上的不同位点。该催化剂还可以耐受氰化物等强亲核试剂，并且可以轻松回收和重复使用。科学，这个问题 p。360; 另见第。320 半导体光催化剂上氧化和还原位点的形成促进了双自由基加成反应。半导体表面上的光激发电子-空穴对可以与两种不同的基材进行氧化还原反应。与传统的电合成类似，主要的氧化还原中间体仅提供单独的氧化和还原产物，或者更罕见地结合成一种加成产物。在这里，我们报告了一种稳定的有机半导体材料，介孔石墨碳氮化物 (mpg-CN)，可以充当可见光光氧化还原催化剂，以协调氧化和还原界面电子转移到两个或三个组件中的两种不同基材。用于芳烃和杂芳烃的直接双重碳氢功能化的系统。mpg-CN
GPR119 Receptor Agonists
申请人：Erickson Shawn David
公开号：US20090286812A1
公开（公告）日：2009-11-19
Provided herein are compounds of the formula (I):
as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
Synthesis and characterization of chelating phenolic polymers containing Metoclopramide hydrochloride drugs
作者：Sameaa Khammas、Selvana Yosef、Tamador Mahmood、Wasan Mahmood、Shahad Taher、Muna Hadi
DOI：10.21608/ejchem.2021.44696.2908
日期：2021.4.25
This study in volved synthesis of the chelating phenolic polymers functionalized by Mannich base functional groups. The work included two parts ; part one syntheses of Mannich bases monomers formed by the condensation reaction of P-hydroxy benzaldehyde with different secondary amines and Primary amine (Metoclopramide hydrochloride) have been synthesized. Then part two included synthesis of phenolic chelating polymers containing Mannich bases by condensation Mannich bases which prepared in part one with P-hydroxy benzaldehyde and phenol. These chelating polymers were characterized through (FT-IR) and( 1H-NMR) spectroscopy so measured the thermal stability and study the biological activity of some of the synthesized compounds .
