钆特酸

钆特酸
临床资料
商品名（英语：Drug nomenclature）	Artirem, Dotarem（多它灵）, Clariscan等
其他名称	DOTA-Gd，Gd-DOTA, Gadoterate meglumine（钆特酸葡胺） (USAN US)
给药途径	静脉注射
ATC码	V08CA02 (WHO) ;
法律规范状态
法律规范	加：处方药（℞-only）; 中：处方药 ; 英：处方药（℞-only） (POM); 美：处方药（℞-only）; 处方药（℞-only）;
药物动力学数据
血浆蛋白结合率	几乎无
药物代谢	几乎无
生物半衰期	约90分钟（血浆）; 2-3分钟（分布）
排泄途径	原体药物经肾，极少部分经粪便排出
识别信息
	IUPAC命名法 gadolinium(3+) 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate; 2-[4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二-1-基]乙酸钆（III）; ;
CAS号	72573-82-1
PubChem CID	158536;
DrugBank	DB09132 ;
ChemSpider	139460;
UNII	QVF9Y6955W;
KEGG	D08007 ;
ChEBI	CHEBI:73732;
ChEMBL	ChEMBL3833326;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID001003675、DTXSID801027873 ;
化学信息
化学式	C16H25GdN4O8
摩尔质量	558.65 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1;
	InChI InChI=1S/C16H28N4O8.Gd/c21-13(22)9-17-1-2-18(10-14(23)24)5-6-20(12-16(27)28)8-7-19(4-3-17)11-15(25)26;/h1-12H2,(H,21,22)(H,23,24)(H,25,26)(H,27,28);/q;+3/p-3; Key:GFSTXYOTEVLASN-UHFFFAOYSA-K;

钆特酸（INN：gadoteric acid，简写Ga-DOTA），为钆离子(Ga³⁺)的大环配体DOTA形成的螯合物。在医学上是一种钆造影剂(gadolinium-based contrast agents，GBCA)，属大环离子型造影剂，用于磁共振成像造影^[2]。其动力学稳定常数 $lgK=25.6$ ，是已知稳定常数和解离半衰期最大的螯合物^[3]^[4]。

医学上常以其葡甲胺盐的形式，即钆特酸葡胺（USAN：Gadoterate meglumine）进行注射给药^[5]^[6]。

历史

钆特酸由法国加柏公司(Guerbet)研制开发，以商品名Dotarem(多它灵)于1989年获准在法国上市，2013年3月20日通过美国FDA批准用于MRI造影^[7]。

同时也是继1982年第一个MRI造影剂马根维显（钆喷酸，Gd-DPTA）问世后的第二个MRI造影剂^[2]。

医学用途

钆特酸中心离子Ga³⁺具有强顺磁性，可缩短磁共振（MRI）中T₁弛豫时间，形成像衬度，为阳性造影剂。但高浓度下T₂弛豫时间缩短占优为阴性造影剂，高浓度常用于动脉期血管造影^[2]。

其被批准用于2岁以上患者的全身MRI检查，可用于大脑、脊髓以及血管检查。其本身无法透过血脑屏障，但大脑血管发生病变部分则可透过血脑屏障，因此可识别脑部肿瘤^[8]。其以钆特酸葡胺注射液形式进行静脉注射，药物可在身体中存在数年^[5]^[6]。

药理学

钆特酸和第一代MRI造影剂马根维显理化性能和临床应用相似。经静脉注射后，钆特酸先经血管扩散，然后迅速扩散细胞外空间。钆特酸通过肾脏以原体药物排泄，少部分分泌到肠胃道经粪便排出。钆特酸非选择性地分布在所有脑外组织的细胞外空间中，无器官特异性。钆特酸蛋白质结合力非常低因此通过肾脏相对较快地排泄。^[2]

风险

钆特酸作为含钆制剂，体外研究表明其具有的神经毒性，但相比于线性钆螯合物，作为大环螯合物的钆特酸相比风险更低^[9]^[10]。在标准用量下，在大脑可检测到药物残留^[11]。

同时具有肾源性系统纤维化(Nephrogenic systemic fibros,NSF)风险，但目前未有相关案例报道，因此不适用于肾功能受损患者^[12]^[13]。

合成

由DOTA与氢氧化钆先在80摄氏度螯合12小时，再用氨水室温下碱化使pH=11即得到钆特酸Ga-DOTA。

+ Ga(OH)₃ →

+3H₂O

钆特酸进一步与葡萄糖和甲胺还原胺化得到的葡甲胺1：1混合成盐，即可得到钆特酸葡胺^[14]^[15]。

（葡萄糖）+

\xrightarrow {\mathrm {H_{2},Ru} }

（葡甲胺）

：+→· （钆特酸葡胺）

参考文献

^ Gadoteric Acid International. Drugs.com. 6 January 2021 [21 January 2021].
^ ^2.0 ^2.1 ^2.2 ^2.3 何国祥; 王毅翔. 造影剂药理学及临床应用. 上海: 上海科学技术出版社. 2002. ISBN 7532362264.
^ P Caravan, JJ Ellison, TJ McMurry, RB Lauffer. Gadolinium (III) chelates as MRI contrast agents: structure, dynamics, and applications. Chemical Reviews. 1999, 99: 2293−2352. doi:10.1021/cr980440x.
^ Herborn, Christoph U. MD; Honold, Elmar MD; Wolf, Michael; Kemper, Jörn MD; Kinner, Sonja MD; Adam, Gerhard MD; Barkhausen, Jörg MD. Clinical Safety and Diagnostic Value of the Gadolinium Chelate Gadoterate Meglumine (Gd-DOTA). Investigative Radiology. 2007, 42 (1): 58–62. doi:10.1097/01.rli.0000248893.01067.e5.
^ ^5.0 ^5.1 Dotarem- gadoterate meglumine injection. DailyMed. [29 August 2021].
^ ^6.0 ^6.1 Clariscan- gadoterate meglumine injection, solution. DailyMed. [29 August 2021].
^ Hollmer M. Dotarem: A safe(r) gadolinium-based contrast imaging agent. FierceBiotech. 6 January 2014.
^ DrugBank (编). Gadoteric acid. DrugBank. 22 August 2016.
^ Bower DV, Richter JK, von Tengg-Kobligk H, Heverhagen JT, Runge VM. Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent. Investigative Radiology. August 2019, 54 (8): 453–463. PMID 31265439. S2CID 164486744. doi:10.1097/RLI.0000000000000567.
^ Alexander Radbruch , Lukas D. Weberling, Pascal J. Kieslich, Oliver Eidel, Sina Burth, Philipp Kickingereder, Sabine Heiland, Wolfgang Wick, Heinz-Peter Schlemmer, Martin Bendszus. Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent. RADIOLOG. 2015, 275 (3): 783–791. doi:10.1148/radiol.2015150337.
^ Stanescu AL, Shaw DW, Murata N, Murata K, Rutledge JC, Maloney E, et al. Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation. Pediatric Radiology. March 2020, 50 (3): 388–396. PMID 31989188. S2CID 210913930. doi:10.1007/s00247-019-04535-w.
^ Todd DJ, Kay J. Gadolinium-Induced Fibrosis. Annual Review of Medicine. 2016, 67: 273–91. PMID 26768242. doi:10.1146/annurev-med-063014-124936.
^ Csilla Balassy, Donna Roberts, Stephen F. Miller3. Safety and efficacy of gadoteric acid in pediatric magnetic resonance imaging: overview of clinical trials and post-marketing studies. Pediatr Radiol. 2015, 45: 1831–1841. doi:10.1007/s00247-015-3394-9.
^ S KauráLuthra, V MorissonáIveson, NE Felicity, J Nicholas. Gd 3+ cFLFLFK conjugate for MRI: a targeted contrast agent for FPR1 in inflammation. Chemical communications. 2013, 49 (6): 564–566. doi:10.1039/C2CC37460A.
^ 韩晓丹,郭春. 钆特酸葡甲胺. 中国药物化学杂志. 2013, 23 (5): 1.

[造影剂-1] Gadoteric Acid International. Drugs.com. 6 January 2021 [21 January 2021].

[造影剂书-2] 2.0 ^2.1 ^2.2 ^2.3 何国祥; 王毅翔. 造影剂药理学及临床应用. 上海: 上海科学技术出版社. 2002. ISBN 7532362264.

[3] P Caravan, JJ Ellison, TJ McMurry, RB Lauffer. Gadolinium (III) chelates as MRI contrast agents: structure, dynamics, and applications. Chemical Reviews. 1999, 99: 2293−2352. doi:10.1021/cr980440x.

[4] Herborn, Christoph U. MD; Honold, Elmar MD; Wolf, Michael; Kemper, Jörn MD; Kinner, Sonja MD; Adam, Gerhard MD; Barkhausen, Jörg MD. Clinical Safety and Diagnostic Value of the Gadolinium Chelate Gadoterate Meglumine (Gd-DOTA). Investigative Radiology. 2007, 42 (1): 58–62. doi:10.1097/01.rli.0000248893.01067.e5.

[Dotarem_FDA_label-5] 5.0 ^5.1 Dotarem- gadoterate meglumine injection. DailyMed. [29 August 2021].

[Clariscan_FDA_label-6] 6.0 ^6.1 Clariscan- gadoterate meglumine injection, solution. DailyMed. [29 August 2021].

[Fierce2014-7] Hollmer M. Dotarem: A safe(r) gadolinium-based contrast imaging agent. FierceBiotech. 6 January 2014.

[2-8] DrugBank (编). Gadoteric acid. DrugBank. 22 August 2016.

[9] Bower DV, Richter JK, von Tengg-Kobligk H, Heverhagen JT, Runge VM. Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent. Investigative Radiology. August 2019, 54 (8): 453–463. PMID 31265439. S2CID 164486744. doi:10.1097/RLI.0000000000000567.

[10] Alexander Radbruch , Lukas D. Weberling, Pascal J. Kieslich, Oliver Eidel, Sina Burth, Philipp Kickingereder, Sabine Heiland, Wolfgang Wick, Heinz-Peter Schlemmer, Martin Bendszus. Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent. RADIOLOG. 2015, 275 (3): 783–791. doi:10.1148/radiol.2015150337.

[11] Stanescu AL, Shaw DW, Murata N, Murata K, Rutledge JC, Maloney E, et al. Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation. Pediatric Radiology. March 2020, 50 (3): 388–396. PMID 31989188. S2CID 210913930. doi:10.1007/s00247-019-04535-w.

[12] Todd DJ, Kay J. Gadolinium-Induced Fibrosis. Annual Review of Medicine. 2016, 67: 273–91. PMID 26768242. doi:10.1146/annurev-med-063014-124936.

[13] Csilla Balassy, Donna Roberts, Stephen F. Miller3. Safety and efficacy of gadoteric acid in pediatric magnetic resonance imaging: overview of clinical trials and post-marketing studies. Pediatr Radiol. 2015, 45: 1831–1841. doi:10.1007/s00247-015-3394-9.

[14] S KauráLuthra, V MorissonáIveson, NE Felicity, J Nicholas. Gd 3+ cFLFLFK conjugate for MRI: a targeted contrast agent for FPR1 in inflammation. Chemical communications. 2013, 49 (6): 564–566. doi:10.1039/C2CC37460A.

[15] 韩晓丹,郭春. 钆特酸葡甲胺. 中国药物化学杂志. 2013, 23 (5): 1.

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