Primarily hepatic. Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by o-oxidation followed by sequential b-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the o-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model.
Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by omega-oxidation followed by sequential beta-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the omega-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. The plasma concentrations of this active metabolite, however, are less than 10% of that of ibutilide.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.
In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces.
来源:DrugBank
吸收、分配和排泄
分布容积
11 升/千克
11 L/kg
来源:DrugBank
吸收、分配和排泄
清除
29毫升/分钟/千克
29 mL/min/kg
来源:DrugBank
吸收、分配和排泄
16名需要恢复正常窦性心律的心房颤动或心房扑动成年患者：6名因左心室功能障碍导致纽约心脏协会（NYHA）二级或三级心力衰竭的患者（平均左心室射血分数（LVEF）为30 ± 9%）；10名没有左心室功能障碍的患者（其中6名患者的平均LVEF为54 ± 5%）作为对照组。所有患者接受了单剂量静脉注射伊布利特1.0毫克，给药时间超过10分钟。在伊布利特给药前、输注结束时以及输注后5、15、30、45分钟和1、1.5、2、3、4、6、8、10、12、24、48小时通过对侧手臂的留置导管获取血样。使用高效液相色谱和质谱法测定血清伊布利特浓度。心力衰竭组和正常左心室功能组在以下参数中没有显著差异：最大血清伊布利特浓度（中位数（四分位距）3.8（2.3-5.7）vs 5.8（3.1-14.4）ug/L，p=0.31），从时间零点到无限大的血清浓度-时间曲线下面积（平均 ± SD 11.0 ± 9.4 vs 13.2 ± 10.6 ug*hr/L，p=0.88），稳态分布体积（1380 ± 334 vs 1390 ± 964 L，p=0.99），系统清除率（129 ± 60 vs 125 ± 81 L/hr，p=0.92）或半衰期（12.5 ± 10.7 vs 12.4 ± 8.6小时，p=0.99）。伊布利特的药代动力学在因左心室收缩功能障碍导致NYHA二级或三级心力衰竭的患者中似乎没有改变。
Sixteen adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm: six patients who had New York Heart Association (NYHA) class II or III heart failure due to left ventricular dysfunction (mean +/- SD left ventricular ejection fraction (LVEF) 30 +/- 9%); 10 patients who did not have left ventricular dysfunction (mean +/- SD LVEF 54 +/- 5% in six of these 10 patients) served as controls. All patients received a single dose of ibutilide 1.0 mg administered intravenously over 10 minutes. Blood samples were obtained through an indwelling catheter in the contralateral arm before ibutilide administration, at the end of the infusion, and at 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after the infusion. Serum ibutilide concentrations were determined by using high-performance liquid chromatography and mass spectrometry. No significant differences were noted between the heart failure and normal left ventricular function groups in the following parameters: maximum serum ibutilide concentration (median (interquartile range) 3.8 (2.3-5.7) vs 5.8 (3.1-14.4) ug/L, p=0.31), area under the serum concentration-time curve from time zero extrapolated to infinity (mean +/- SD 11.0 +/- 9.4 vs 13.2 +/- 10.6 ug*hr/L, p=0.88), steady-state volume of distribution (1380 +/- 334 vs 1390 +/- 964 L, p=0.99), systemic clearance (129 +/- 60 vs 125 +/- 81 L/hr, p=0.92), or half-life (12.5 +/- 10.7 vs 12.4 +/- 8.6 hrs, p=0.99). The pharmacokinetics of ibutilide do not appear to be altered in patients with NYHA class II or III heart failure due to left ventricular systolic dysfunction.
A Multicatalytic Approach to the Hydroaminomethylation of α‐Olefins
作者：Steven Hanna、Jeffrey C. Holder、John F. Hartwig
DOI：10.1002/anie.201811297
日期：2019.3.11
reductive amination step, which is conducted as a transfer hydrogenation with aqueous, buffered sodium formate as the reducing agent, is catalyzed by a cyclometallated iridium complex. By adjusting the ratio of CO to H2, we conducted the reaction at one atmosphere of gas with little change in yield. A diverse array of olefins and amines, including hetreroarylamines that do not react under more conventional
Methanesulfonamides are structurally depicted by Formula I' ##STR1## or its pharmacologically acceptable salts where R.sub.3 is a C.sub.1-7 alkyl substituted with C.sub.3-7 cycloalkyl, or a C.sub.1-10 alkyl substituted with one to eight fluorine atoms, one to three hydroxy, one to three C.sub.1-5 acyloxy or one to three C.sub.1-4 alkoxy substituents. These compounds are useful as Class III antiarrhythmic agents and are stable against rapid metabolism. Methods for treating cardiac arrhythmias with the compounds of Formula I' as well as compositions thereof are also described.
Racemization and Intramolecular Nucleophilic Substitution Reactions of Ibutilide
作者：William J. Lambert、Paula G. Timmer、Rodney R. Walters、Chang‐Yuan L. Hsu
DOI：10.1002/jps.2600811015
日期：1992.10
The kinetics and mechanisms of the racemization and cyclization reactions of ibutilide are described. The cyclization reaction yields a bell-shaped rate-pH curve consistent with a change in rate-determiningstep. It is hypothesized that the hydroxyl group leaves to form a carbocation intermediate; this is followed by nucleophilic attack by the amine. This mechanism is supported by kinetic analysis
Antiarrhythmic N-aminoalkylene alkyl and aryl sulfonamides
申请人：The Upjohn Company
公开号：US05155268A1
公开（公告）日：1992-10-13
The present invention provides novel sulfonanilide and benzene-alkylaminium compounds which are the products of processes utilizing novel intermediates. Both the novel compounds and the novel intermediates are useful for the therapeutic or prophylactic treatment of arrhythmic activity.
Compounds for the treatment of mitochondrial diseases
申请人：UNIVERSITE PARIS-SUD
公开号：US10639287B2
公开（公告）日：2020-05-05
Disclosed is a compound of formula (Ia) for the use thereof in the treatment or prevention of diseases relating to the instability of mitochondrial DNA.
