Liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Age and gender do not substantially affect the pharmacodynamic or pharmacokinetic profile of argatroban.
The main route of argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of each of the 4 known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. The primary metabolite (M1) exerts 3- to 5-fold weaker anticoagulant effects than argatroban. Unchanged argatroban is the major component in plasma. The plasma concentrations of M1 range between 0% and 20% of that of the parent drug. The other metabolites (M2 to M4) are found only in very low quantities in the urine and have not been detected in plasma or feces. These data, together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not an important elimination pathway in vivo.
来源:Hazardous Substances Data Bank (HSDB)
代谢
阿加曲班主要通过肝脏代谢，通过3-甲基四氢喹啉环的羟基化和芳香化来进行。
Argatroban is metabolized principally by the liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring.
IDENTIFICATION AND USE: Argatroban is antithrombin, platelet aggregation inhibitor. Direct thrombin inhibitors including argatroban are commonly used anticoagulants in patients with known or suspected heparin-induced thrombocytopenia. HUMAN STUDIES: There are two case reports documenting safe use of argatroban during human pregnancy. Argatroban was not genotoxic in the WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) test. ANIMAL STUDIES: Single intravenous doses of argatroban at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma. Developmental studies performed in rats (during gestation Days 7 to 17) with argatroban at intravenous doses up to 27 mg/kg/day and in rabbits (during gestation Days 6 to 18) at intravenous doses up to 10.8 mg/kg/day have revealed no evidence of harm to the fetus. Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte or the mouse micronucleus test.
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
Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which (14)C-argatroban (5 ug/kg/min) was infused for 4 hours into healthy subjects, approximately 65% of the radioactivity was recovered in the feces within 6 days of the start of infusion with little or no radioactivity subsequently detected. Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start of infusion. Little or no additional urinary radioactivity was subsequently detected. Average percent recovery of unchanged drug, relative to total dose, was 16% in urine and at least 14% in feces.
Argatroban was synthesized in seven steps from 4-methylpiperidine. The condensation of (+/-)-trans-benzyl 4-methyl-pipecolic acid ester with N-alpha-Boc-N-omega-nitro-L-arginine led to two diastereomers that were separated. One of them is the precursor of argatroban. (C) 2001 Elsevier Science Ltd. All rights reserved.
Efficient Diastereoselective Three‐Component Synthesis of Pipecolic Amides
作者：Gydo van der Heijden、Timo B. van Schaik、Valentinos Mouarrawis、Martin J. M. de Wit、Christophe M. L. Vande Velde、Eelco Ruijter、Romano V. A. Orru
DOI：10.1002/ejoc.201900399
日期：2019.9
An efficient Ugi-type three-component reaction (U-3CR) for the synthesis of pipecolic amides is reported. The U-3CR between electronically diverse isocyanides, carboxylic acids and 4-substituted Δ1-piperideines proceeds in a highly diastereoselective fashion. The Δ1-piperideines are obtained by NCS-mediated oxidation of the corresponding 4-substituted piperidines, which in turn are generated by an
HYDROPHILIC POLYMER COMPOUND HAVING ANTICOAGULATION EFFECT
申请人：Sakaguchi Hirokazu
公开号：US20120271010A1
公开（公告）日：2012-10-25
A hydrophilic polymer compound includes a polymer compound which inhibits platelet adhesion, and a compound that inhibits blood coagulation reaction, bound to the polymer compound.
Method for preparing argatroban monohydrate and a process for its synthesis
申请人：Zanon Jacopo
公开号：US08378106B2
公开（公告）日：2013-02-19
A method is described for preparing argatroban monohydrate obtained from (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinesulphonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid by suitably treating crude argatroban. The method either comprises preparation of argatroban monohydrate in a continuous step or an intermediate step of isolating a purified argatroban. Also obtainable from argatroban monohydrate is anhydrous argatroban, shown to have new physico-chemical characteristics.
The described argatroban synthesis and purification process hence enables three different forms of argatroban, not previously described, to be obtained, each with distinctive physico-chemical characteristics and in particular enables argatroban monohydrate to be obtained with high yield and with high purity, being therefore a product suitable for use as active principle in proprietary medicines.
An instrument captures free thrombi by inhibiting blood coagulation reaction at the stage of primary hemostasis, in which platelets are involved, and at the stage of coagulation thrombus formation, in which blood coagulation factors are involved, thereby securely capturing free thrombi and extending the available time of the instrument.
COMPOSITIONS AND METHODS FOR PRESERVING PLATELET FUNCTION
申请人：BIOVEC TRANSFUSION, LLC
公开号：US20150056604A1
公开（公告）日：2015-02-26
Compositions and methods for maintaining platelet functionality and extending the shelf-life of platelets are described. Platelet preservation compositions include a photosensitizer and a plurality of platelet preservation agents. A method for preserving platelets and extending their shelf-life includes irradiating a platelet mixture containing a photosensitizer under conditions sufficient to activate the photosensitizer and inactivate microbes in the platelet mixture to form a microbe-depleted platelet preparation. A plurality of platelet preservation agents are added to the microbe-depleted platelet preparation for extending the platelet shelf-life. Prior to transfusion, the photosensitizer and platelet preservation agents can be removed by diafiltration and/or the use of compound adsorption devices.
