釓特酸

釓特酸
臨床資料
商品名（英語：Drug nomenclature）	Artirem, Dotarem（多它靈）, Clariscan等
其他名稱	DOTA-Gd，Gd-DOTA, Gadoterate meglumine（釓特酸葡胺） (USAN US)
給藥途徑	靜脈注射
ATC碼	V08CA02 (WHO) ;
法律規範狀態
法律規範	加：處方藥（℞-only）; 中：處方藥 ; 英：處方藥（℞-only） (POM); 美：處方藥（℞-only）; 處方藥（℞-only）;
藥物動力學數據
血漿蛋白結合率	幾乎無
藥物代謝	幾乎無
生物半衰期	約90分鐘（血漿）; 2-3分鐘（分布）
排泄途徑	原體藥物經腎，極少部分經糞便排出
識別資訊
	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)-1,4,7,10-四氮雜環十二-1-基]乙酸釓（III）; ;
CAS號	72573-82-1
PubChem CID	158536;
DrugBank	DB09132 ;
ChemSpider	139460;
UNII	QVF9Y6955W;
KEGG	D08007 ;
ChEBI	CHEBI:73732;
ChEMBL	ChEMBL3833326;
CompTox Dashboard（英語：CompTox Chemicals Dashboard） (EPA)	DTXSID001003675、DTXSID801027873 ;
化學資訊
化學式	C16H25GdN4O8
摩爾質量	558.65 g·mol−1
3D模型（JSmol（英語：JSmol））	交互式圖像;
	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;

釓特酸（INN：gadoteric acid，簡寫Ga-DOTA），為釓離子(Ga³⁺)的大環配體DOTA形成的螯合物。在醫學上是一種釓造影劑(gadolinium-based contrast agents，GBCA)，屬大環離子型造影劑，用於磁共振成像造影^[2]。其動力學穩定常數 $lgK=25.6$ ，是已知穩定常數和解離半衰期最大的螯合物^[3]^[4]。

醫學上常以其葡甲胺鹽的形式，即釓特酸葡胺（USAN：Gadoterate meglumine）進行注射給藥^[5]^[6]。

歷史

釓特酸由法國加柏公司(Guerbet)研製開發，以商品名Dotarem(多它靈)於1989年獲准在法國上市，2013年3月20日通過美國FDA批准用於MRI造影^[7]。

同時也是繼1982年第一個MRI造影劑馬根維顯（釓噴酸，Gd-DPTA）問世後的第二個MRI造影劑^[2]。

醫學用途

釓特酸中心離子Ga³⁺具有強順磁性，可縮短磁共振（MRI）中T₁弛豫時間，形成像襯度，為陽性造影劑。但高濃度下T₂弛豫時間縮短占優為陰性造影劑，高濃度常用於動脈期血管造影^[2]。

其被批准用於2歲以上患者的全身MRI檢查，可用於大腦、脊髓以及血管檢查。其本身無法透過血腦屏障，但大腦血管發生病變部分則可透過血腦屏障，因此可識別腦部腫瘤^[8]。其以釓特酸葡胺注射液形式進行靜脈注射，藥物可在身體中存在數年^[5]^[6]。

藥理學

釓特酸和第一代MRI造影劑馬根維顯理化性能和臨床應用相似。經靜脈注射後，釓特酸先經血管擴散，然後迅速擴散細胞外空間。釓特酸通過腎臟以原體藥物排泄，少部分分泌到腸胃道經糞便排出。釓特酸非選擇性地分布在所有腦外組織的細胞外空間中，無器官特異性。釓特酸蛋白質結合力非常低因此通過腎臟相對較快地排泄。^[2]

風險

釓特酸作為含釓製劑，體外研究表明其具有的神經毒性，但相比於線性釓螯合物，作為大環螯合物的釓特酸相比風險更低^[9]^[10]。在標準用量下，在大腦可檢測到藥物殘留^[11]。

同時具有腎源性系統纖維化(Nephrogenic systemic fibros,NSF)風險，但目前未有相關案例報道，因此不適用於腎功能受損患者^[12]^[13]。

合成

由DOTA與氫氧化釓先在80攝氏度螯合12小時，再用氨水室溫下鹼化使pH=11即得到釓特酸Ga-DOTA。

+ Ga(OH)₃ →

+3H₂O

釓特酸進一步與葡萄糖和甲胺還原胺化得到的葡甲胺1：1混合成鹽，即可得到釓特酸葡胺^[14]^[15]。

（葡萄糖）+

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

（葡甲胺）

：+→· （釓特酸葡胺）

參考文獻

^ Gadoteric Acid International. Drugs.com. 6 January 2021 [21 January 2021].
^ ^2.0 ^2.1 ^2.2 ^2.3 何國祥; 王毅翔. 造影剂药理学及临床应用. 上海: 上海科學技術出版社. 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 (編). 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.
^ 韓曉丹,郭春. 钆特酸葡甲胺. 中國藥物化學雜誌. 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 何國祥; 王毅翔. 造影剂药理学及临床应用. 上海: 上海科學技術出版社. 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 (編). 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] 韓曉丹,郭春. 钆特酸葡甲胺. 中國藥物化學雜誌. 2013, 23 (5): 1.

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