This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown.
来源:DrugBank
代谢
胺碘酮已知的人体代谢产物包括N-脱乙基胺碘酮。
Amiodarone has known human metabolites that include N-Desethylamiodarone.
Amiodarone is extensively metabolized in the liver via CYP2C8 (under 1% unchanged in urine), and can effect the metabolism of numerous other drugs. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone.
Route of Elimination: Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine.
Half Life: 58 days (range 15-142 days)
The antiarrhythmic effect of amiodarone may be due to at least two major actions. It prolongs the myocardial cell-action potential (phase 3) duration and refractory period and acts as a noncompetitive a- and b-adrenergic inhibitor.
While liver injury from amiodarone is uncommon but not rare. Serum enzyme elevations are reported to occur in 15% to 50% of patients on long term therapy, but with lower doses (200 to 300 mg daily), ALT elevations are less common. Often these elevations resolve despite continuation of amiodarone, and liver biopsy may reveal minimal changes, or accumulation of granular material in macrophages without other evidence of injury. Patients taking amiodarone are recommended to have ALT and AST values taken at baseline and then every six months, and to discontinue therapy if levels are persistently greater than twice the upper limit of the normal range. The efficacy of this approach, even if followed, in preventing serious liver injury from amiodarone is unclear.
Clinically apparent liver disease arises in up to 1% of amiodarone treated patients annually. The liver injury occurs more frequently with higher doses and prolonged therapy, and total cumulative dosage may be important as amiodarone can accumulate and can persist in liver tissue, even long after therapy is stopped. Typically, patients develop symptoms of fatigue, nausea and weight loss without jaundice and are found to have hepatomegaly and mild-to-moderate elevations in serum aminotransferase and alkaline phosphatase levels. Jaundice can occur but is mild; however, with severe injury, jaundice can progress and there may be prolongation of the prothrombin time and fall in serum albumin levels, and development of signs and symptoms of end stage liver disease with progressive weakness, weight loss, ascites, and hepatic encephalopathy (Cases 1 and 2). The injury resembles alcoholic liver disease clinically and histologically, although serum ALT and AST are usually elevated to a similar degree in amiodarone toxicity in contrast to alcoholic liver injury. Like in alcoholic liver disease, the ALT elevations are generally modest with normal or minimally elevated alkaline phosphatase levels. However, the pattern of enzyme elevations can vary from marked ALT elevations in a hepatocellular injury pattern, to minimal ALT increases with more prominent alkaline phosphatase elevations in a cholestatic pattern. The injury resolves slowly after stopping therapy and in some cases progresses for a period despite discontinuation. Liver biopsy shows variable findings; early there is micro- and macrovesicular fat, ballooning degeneration, and mild inflammation, whereas later there is moderate inflammation (sometimes granulomatous) and variable amounts of fibrosis and Mallory bodies but little steatosis. Electron microscopy reveals characteristic abnormal mitochondria and phospholipid laden lysosomes (seen on light microscopy as granular cells), but these changes can be observed even in the absence of significant liver injury. The liver is often bright on CT scan without contrast, due to accumulation of the iodinated drug and not necessarily indicating liver injury. Amiodarone and its derivatives can be detected in plasma and in hepatic tissue, and these levels may remain high for months if not years after stopping.
Amiodarone has also been associated with rare cases of Reye Syndrome, usually arising in a child on chronic amiodarone therapy who develops an acute viral syndrome suggesting influenza. Amiodarone, like aspirin, has been shown to interfere with mitochondrial function, which may be the basis for the acute injury resembling Reye syndrome in susceptible children.
Finally, amiodarone is capable of causing a distinctly different form of liver injury when it is given intravenously, particularly if given in high doses to elderly or frail patients (Cases 3 and 4). Serum ALT and AST can be markedly elevated (10 to 100 fold) within a day of the infusion, with minimal increases in alkaline phosphatase. Renal insufficiency can also occur. Usually, the liver injury reverses quickly with stopping the infusion, with ALT and AST falling into the normal range within days. In rare instances, jaundice and even acute liver failure have occurred shortly after initiating intravenous amiodarone therapy. Importantly, the mechanism of injury in this acute situation is probably different than in chronic exposure, and patients with acute hepatic injury following intravenous infusions of amiodarone can usually tolerate oral therapy without complications. However, reexposure to intravenous amiodarone is usually followed by reappearance of the acute injury.
Likelihood score: A (well established cause of clinically apparent liver injury).
The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%.
来源:DrugBank
吸收、分配和排泄
消除途径
肝代谢和胆汁排泄是阿米奥达龙主要的消除途径。尿液中可检测到少量脱乙基阿米奥达龙（DEA）。
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine.
In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone.
The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction.
建立了一种快速高效液相色谱测定法，用于测定血浆，尿液和胆汁中的胺碘酮（1）及其N-去乙基代谢产物（去乙基胺碘酮，2）。使用由甲醇：水：58％氢氧化铵（94：4：2）组成的流动相，以1.5 mL / min的流速进样，在C18反相柱和预柱上进行分析。在244nm下监测洗脱液。在这些条件下，1，2，和内标物的洗脱时间分别为5.5、4.6和6.8分钟。通过用含有内标的乙腈沉淀血浆蛋白，然后将等分试样的上清液直接注入色谱柱中，制备血浆样品（100微升）。通过用浓盐酸酸化样品，然后用六倍体积的2，2-二甲氧基丙烷萃取混合物，来制备用于注射的尿液和胆汁样品（100微升）。从血浆中回收1和2实际上已完成。尿液和胆汁的回收率分别为1的80-90％和2的60-65％。两种化合物在血浆中的敏感性极限为100 ng / mL。对于尿液和胆汁，检出限分别为1和5微克/ mL。在0.1-10.0微克/ mL的血
[EN] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
申请人：VPS 3 INC
公开号：WO2018165520A1
公开（公告）日：2018-09-13
Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
申请人：Arvinas, Inc.
公开号：US20180125821A1
公开（公告）日：2018-05-10
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
[EN] TARGETING COMPOUNDS<br/>[FR] COMPOSÉS DE CIBLAGE
申请人：ZAFGEN INC
公开号：WO2019118612A1
公开（公告）日：2019-06-20
The disclosure provides, at least in part, liver, intestine and/or kidney-targeting compounds and their use in treating liver, intestine and/or kidney disorders, such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, hepatocellular carcinoma, liver cirrhosis, and hepatitis B; and/or chronic kidney disease, glomerular disease such as IGA nephropathy, lupus nephritis, or polycystic kidney disease. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.
