钆喷酸

钆喷酸
臨床資料
商品名（英语：Drug nomenclature）	Magnevist（马根维显）
其他名稱	Gd-DTPA、SHL-451A; gadopentetate dimeglumine（磁显葡胺）
AHFS/Drugs.com	消费者药物信息
给药途径	静脉注射
ATC碼	V08CA01 (WHO) ;
法律規範狀態
法律規範	中：处方药 ; 歐：Rx-only; 美：处方药（℞-only）;
藥物動力學數據
生物半衰期	分布半衰期：12分钟; 清除半衰期：100分钟
识别信息
CAS号	86050-77-3
PubChem CID	6857474;
DrugBank	DB00789 ;
ChemSpider	50087 ;
UNII	RH248G8V27;
KEGG	D01707 ;
ChEBI	CHEBI:31797 ;
ChEMBL	ChEMBL1200431 ;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID70235367 ;
化学信息
化学式	C14H18GdN3O10
摩尔质量	545.56 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES [Gd+3].[O-]C(=O)CN(CCN(CC(=O)O)CC([O-])=O)CCN(CC([O-])=O)CC(=O)O.O[C@H]([C@@H](O)CNC)[C@H](O)[C@H](O)CO.O[C@@H](CNC)[C@@H](O)[C@H](O)[C@H](O)CO;
	InChI InChI=1S/C14H23N3O10.2C7H17NO5.Gd/c18-10(19)5-15(1-3-16(6-11(20)21)7-12(22)23)2-4-17(8-13(24)25)9-14(26)27;21-8-2-4(10)6(12)7(13)5(11)3-9;/h1-9H2,(H,18,19)(H,20,21)(H,22,23)(H,24,25)(H,26,27);24-13H,2-3H2,1H3;/q;;;+3/p-3/t;2*4-,5+,6+,7+;/m.00./s1 ; Key:LGMLJQFQKXPRGA-VPVMAENOSA-K ;

钆喷酸（INN：gadopentetic acid）,化学式：C₁₄H₁₈GdN₃O₁₀，为Ga³⁺与二乙三胺五乙酸（英语：Pentetic acid）（DTPA）的螯合物，因此可表示为Ga-DTPA。为首个用于临床的磁共振成像（MRI）造影剂，商品名为马根维显（Magnevist）^[1]。

临床上采用其葡甲胺盐形式进行注射给药，即钆喷酸葡胺（USAN：gadopentetate dimeglumine，钆喷酸二葡甲胺）（旧称磁显葡胺^[2]）。其在血脑屏障破裂处和血管、血流动力学方面具有较高的灵敏度^[3]，同时也是目前临床最常用的核磁共振成像造影剂之一^[4]^[5]。

历史

钆喷酸由1981年德国先灵(Schering AG)制药公司的Hanns-Joachim Weinmann和其同事首次发现^[6] ，1983年Weinmann与Brasch首次应用于脑部肿瘤诊断，1987年通过美国FDA认证^[7]，同时开启了MRI造影剂的研究历程^[1]。

2017年7月，因为长期使用钆喷酸会造成钆脑部沉积，欧洲药品管理局建议其成员国暂停批准包括马根维显在内的线性结构钆造影剂用于全身使用。^[8]^[9]^[10]

结构性质

钆喷酸属线性螯合物，其动力学络合稳定常数 $lgK$ =22.46^[11]。

钆喷酸中心离子Ga³⁺配位数为9，螯合配体二乙三胺五乙酸拥有3个氮原子和五个羧基氧配齿与Ga³⁺螯合，剩余的Ga³⁺配位数与水分子氧进行配位^[12]。螯合配体与Ga³⁺形成变形三帽三棱柱几何结构,Ga-O_水键长略长于Ga-O_羧基，Ga-N_中心键长略短于Ga-N_两侧。不同阳离子的钆喷酸盐咬角介于理想四角反棱柱和理想三帽三棱柱（英语：Tricapped trigonal prismatic molecular geometry）之间^[11]。

Ga³⁺外层电子轨道含有7对自旋平行的未成对电子，⁸S电子基态使得Ga³⁺具有强顺磁性。水分子与顺磁性的Ga³⁺可逆结合在氢核磁共振中产生内界弛豫，影响T₁和T₂弛豫时间，造成MRI像衬度。^[13]

MRI造影剂

原理

钆喷酸为离子型钆基造影剂，高络合稳定常数使得在体内很稳定，脱螯出有毒的Ga³⁺可忽略不计^[14]^[15]。 Ga³⁺的强顺磁性使得钆喷酸为阳性显影剂。Gd³⁺配位数为9，然而配体DTPA配位数为8，因此剩余的位点与水分子可逆结合在氢核磁共振中产生内界弛豫，减小和自旋-晶格弛豫时间T₁和自旋-自旋弛豫时间T₂，但T₁弛豫时间减小占比更优(T₁弛豫效率=4 mM^-1s^-1；T₂弛豫效率=6 mM^-1s^-1)，使得T₁加权图像更亮，形成对比度^[4]。

作用

静脉注射后，钆喷酸迅速扩散到血液和细胞外空间，其分布无器官专一性，与各组织供血和毛细血管通透性有关。分布半衰期12分钟，清除半衰期100分钟，药物原体经肾从尿液排出，少部分会分泌到胃肠道经粪便排出^[4]。作为一种高极性且相对较大的分子，钆喷酸在静脉注射后无法穿过脑部、睾丸、眼部等有毛细血管屏障的器官，因此其无法正常透过健康人体的血脑屏障，若血管异常或有血脑屏障异常的颅内病变（如胶质母细胞瘤），钆喷酸则会在病变部位透过血脑屏障，MRI图像上相应部分产生高亮。因此钆喷酸可用于识别血管病变和脑部肿瘤^[16]。

钆喷酸葡胺注射到关节中可进行延迟钆增强磁共振软骨成像（dGEMRIC（英语：Delayed gadolinium-enhanced magnetic resonance imaging of cartilage）），因钆喷酸葡胺独特的电子结构可实现逆向测量自旋-晶格弛豫时间T₁，这是因为T₁与软骨中蛋白聚糖聚集体浓度以及糖胺聚糖带电侧基有关^[17]^[18]。

风险

作为含钆制剂，患有严重肾脏疾病以及肾功能不全的患者使用钆喷酸会引起肾源性系统性纤维化，因此该类人群被限制使用钆喷酸以及相关含钆显影剂。^[19]^[20]。长期使用会造成钆脑部沉积^[9]^[10]。同时其不良发生率很低，但有既往有含碘显影剂以及含钆显影剂相关过敏史、以及含有基础疾病的使用者发生不良反应风险会增加^[21]^[19]。

参考文献

^ ^1.0 ^1.1 潘博. 核磁共振成像对比增强造影剂的研究进展. 世界最新医学信息文摘. 2016, 16 (30): 38–39. doi:10.3969/j.issn.1671-3141.2016.30.023.
^ 张冬,冯晓源,王从俭. 磁显葡胺含量测定方法的建立. 中国医学计算机成像杂志. 2005, (1): 65–67. doi:10.19627/j.cnki.cn31-1700/th.2005.01.016.
^ M Aschner, JL Aschner. Manganese transport across the blood-brain barrier: relationship to iron homeostasis. Brain research bulletin. 1990, 24 (6): 857–860. doi:10.1016/0361-9230(90)90152-P.
^ ^4.0 ^4.1 ^4.2 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.
^ 于兆臻，黄建雨，周赞民，李晓伟. 核磁共振成像造影剂的发展现状. 山东化工. 2019, 48 (21): 60–62+67. doi:10.19319/j.cnki.issn.1008-021x.2019.21.023.
^ US 5021236,「Method of enhancing NMR imaging using chelated paramagnetic ions bound to biomolecules」
^ H Yim, SG Yang, YS Jeon, IS Park, M Kim, DH Lee, YH Bae, K Na. The performance of gadolinium diethylene triamine pentaacetate-pullulan hepatocyte-specific T1 contrast agent for MRI. Biomaterials. 2011, 32 (22): 5187–5194. doi:10.1016/j.biomaterials.2011.03.069.
^ European Medicines Agency: Gadolinium-containing contrast agents ema.europa.eu
^ ^9.0 ^9.1 Gadolinium-containing contrast agents: removal of Omniscan and iv Magnevist, restrictions to the use of other linear agents. GOV.UK. 14 December 2017 [29 August 2021].
^ ^10.0 ^10.1 EU pulls gadolinium contrast agents over deposition concerns. www.radiologybusiness.com. [18 August 2020].
^ ^11.0 ^11.1 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.
^ Sherry AD, Caravan P, Lenkinski RE. Primer on gadolinium chemistry. Journal of Magnetic Resonance Imaging. 2009, 30 (6): 1240–1248. PMID 19938036. doi:10.1002/jmri.21966.
^ Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chemical Reviews. September 1999, 99 (9): 2293–2352. PMID 11749483. doi:10.1021/cr980440x.
^ 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.
^ H. Scholz, G. Kuschinsky, R. H. Böger: Taschenbuch der Arzneibehandlung. Springer, 2005, S. 606. (《钆喷酸》在Google Books的內容。)
^ Bashir A, Gray ML, Boutin RD, Burstein D. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd(DTPA)(2-)-enhanced MR imaging. Radiology. November 1997, 205 (2): 551–558. PMID 9356644. doi:10.1148/radiology.205.2.9356644.
^ Bashir A, Gray ML, Hartke J, Burstein D. Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI. Magnetic Resonance in Medicine. May 1999, 41 (5): 857–865. PMID 10332865. S2CID 22939233. doi:10.1002/(sici)1522-2594(199905)41:5<857::aid-mrm1>3.0.co;2-e .
^ ^19.0 ^19.1 Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR. American Journal of Roentgenology. October 1996, 167 (4): 847–849. PMID 8819369. doi:10.2214/ajr.167.4.8819369 .
^ Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)?. Clinical Radiology. November 2006, 61 (11): 905–906. PMID 17018301. doi:10.1016/j.crad.2006.09.003.
^ 周庆春. 189例磁共振对比剂钆喷酸普胺致不良反应病例的文献分析. 抗感染药学. 2016, 13 (1): 118–120. doi:10.13493/j.issn.1672-7878.2016.01-041.

[进展-1] 1.0 ^1.1 潘博. 核磁共振成像对比增强造影剂的研究进展. 世界最新医学信息文摘. 2016, 16 (30): 38–39. doi:10.3969/j.issn.1671-3141.2016.30.023.

[2] 张冬,冯晓源,王从俭. 磁显葡胺含量测定方法的建立. 中国医学计算机成像杂志. 2005, (1): 65–67. doi:10.19627/j.cnki.cn31-1700/th.2005.01.016.

[3] M Aschner, JL Aschner. Manganese transport across the blood-brain barrier: relationship to iron homeostasis. Brain research bulletin. 1990, 24 (6): 857–860. doi:10.1016/0361-9230(90)90152-P.

[造影剂书-4] 4.0 ^4.1 ^4.2 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.

[5] 于兆臻，黄建雨，周赞民，李晓伟. 核磁共振成像造影剂的发展现状. 山东化工. 2019, 48 (21): 60–62+67. doi:10.19319/j.cnki.issn.1008-021x.2019.21.023.

[6] US 5021236,「Method of enhancing NMR imaging using chelated paramagnetic ions bound to biomolecules」

[7] H Yim, SG Yang, YS Jeon, IS Park, M Kim, DH Lee, YH Bae, K Na. The performance of gadolinium diethylene triamine pentaacetate-pullulan hepatocyte-specific T1 contrast agent for MRI. Biomaterials. 2011, 32 (22): 5187–5194. doi:10.1016/j.biomaterials.2011.03.069.

[8] European Medicines Agency: Gadolinium-containing contrast agents ema.europa.eu

[被禁1-9] 9.0 ^9.1 Gadolinium-containing contrast agents: removal of Omniscan and iv Magnevist, restrictions to the use of other linear agents. GOV.UK. 14 December 2017 [29 August 2021].

[被禁2-10] 10.0 ^10.1 EU pulls gadolinium contrast agents over deposition concerns. www.radiologybusiness.com. [18 August 2020].

[Ga综述-11] 11.0 ^11.1 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.

[12] Sherry AD, Caravan P, Lenkinski RE. Primer on gadolinium chemistry. Journal of Magnetic Resonance Imaging. 2009, 30 (6): 1240–1248. PMID 19938036. doi:10.1002/jmri.21966.

[13] Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chemical Reviews. September 1999, 99 (9): 2293–2352. PMID 11749483. doi:10.1021/cr980440x.

[14] 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.

[15] 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.

[16] H. Scholz, G. Kuschinsky, R. H. Böger: Taschenbuch der Arzneibehandlung. Springer, 2005, S. 606. (《钆喷酸》在Google Books的內容。)

[17] Bashir A, Gray ML, Boutin RD, Burstein D. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd(DTPA)(2-)-enhanced MR imaging. Radiology. November 1997, 205 (2): 551–558. PMID 9356644. doi:10.1148/radiology.205.2.9356644.

[18] Bashir A, Gray ML, Hartke J, Burstein D. Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI. Magnetic Resonance in Medicine. May 1999, 41 (5): 857–865. PMID 10332865. S2CID 22939233. doi:10.1002/(sici)1522-2594(199905)41:5<857::aid-mrm1>3.0.co;2-e .

[murphy-19] 19.0 ^19.1 Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR. American Journal of Roentgenology. October 1996, 167 (4): 847–849. PMID 8819369. doi:10.2214/ajr.167.4.8819369 .

[thomsen-20] Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)?. Clinical Radiology. November 2006, 61 (11): 905–906. PMID 17018301. doi:10.1016/j.crad.2006.09.003.

[21] 周庆春. 189例磁共振对比剂钆喷酸普胺致不良反应病例的文献分析. 抗感染药学. 2016, 13 (1): 118–120. doi:10.13493/j.issn.1672-7878.2016.01-041.

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