Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid
Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid
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DOI：
10.1097/rli.0b013e3182a70043
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发表时间：
2014-02-01
影响因子：
6.7
通讯作者：
Keiser, Markus
中科院分区：
文献类型：
--
作者：
Jia, Jia;Puls, Dorothee;Keiser, Markus
目的研究钆塞酸酯的药代动力学和肝脏增强作用（钆-乙基苄基-二亚乙基三胺-五乙酸[Gd-EOB-DTPA]，Eovist，Primovist）口服和静脉内给药后，（多药耐药相关蛋白2）Mrp 2-缺陷的大鼠，并评估造影剂通过肠和肝转运蛋白的体外转运。分别使用T1加权磁共振成像和经验证的液相色谱-质谱法，在野生型和Mrp 2缺陷大鼠中评价静脉和口服给药后钆-乙硫基苄基-二乙烯三胺-五乙酸增强磁共振成像和Gd-EOB-DTPA的药代动力学。在表达有机阴离子转运多肽1A 2或有机阳离子转运蛋白3的稳定转染的人胚胎肾293细胞和表达顶端钠依赖性胆汁酸转运蛋白的Madin达比犬肾2细胞中测定了Gd-EOB-DTPA的细胞摄取。结果Gd-EOB-DTPA在体外可作为OATP 1A 2的底物（米氏常数[K-m]的平均值[SD]，1.0 [0.4] mmol/L;最大摄取速率[V-max]的平均值[SD]，101.3 [21.1] pmol/mg/min），MRP 2（K-m，1.0 [0.5] mmol/L; V-max，86.8 [31.1] pmol/mg/min）和多药耐药相关蛋白3（K-m，1.8 [0.3] mmol/L; V-max，116 [15.9] pmol/mg/min），但不包括顶端钠依赖性胆汁酸转运蛋白和有机阳离子转运蛋白3。野生型动物经口给药后，Gd-EOB-DTPA从小肠中大量吸收（生物利用度约为17%），静脉给药后主要通过粪便消除（约为96%）。在Mrp 2缺陷大鼠中，口服生物利用度增加至约21%，Gd-EOB-DTPA仅经尿液排泄。与野生型大鼠相比，Mrp 2缺陷大鼠肝脏的磁共振增强显著延长（平均[SD]曲线下面积（0-90），36.4 [8.5] vs 14.8 [10.3]任意单位/分钟; P = 0.003;达峰时间，48.6 [23.8] vs 6.0 [3.1]分钟;结论非代谢型Gd-EOB-DTPA可作为一种潜在的探针造影剂，通过功能显像研究药物在体内的沿着肠肝吸收途径的转运蛋白介导机制。
Objectives The objectives of the study were to measure the pharmacokinetics and liver enhancement of gadoxetate (gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid [Gd-EOB-DTPA], Eovist, Primovist) after oral and intravenous administration in wild-type and (multidrug resistance-associated protein 2) Mrp2-deficient rats and to evaluate the in vitro transport of the contrast agent via intestinal and hepatic transporter proteins.Materials and Methods Gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging and pharmacokinetics of Gd-EOB-DTPA after intravenous and oral administration were evaluated in wild-type and Mrp2-deficient rats using T1-weighted magnetic resonance imaging and a validated liquid chromatography-mass spectrometry method, respectively. Cellular uptake of Gd-EOB-DTPA was measured in stably transfected human embrionic kidney 293-cells expressing oragnic anion-transporting polypeptide 1A2 or organic cation transporter 3 and Madin Darby canine kidney 2-cells expressing apical sodium dependent bile acid transporter. The affinity to MRP2 and multidrug resistance-associated protein 3 was measured using inside-out vesicles.Results In vitro, Gd-EOB-DTPA was demonstrated to be a substrate for OATP1A2 (mean [SD] of the Michaelis-Menten constant [K-m], 1.0 [0.4] mmol/L; mean [SD] of the maximal uptake rate [V-max], 101.3 [21.1] pmol/mg per minute), MRP2 (K-m, 1.0 [0.5] mmol/L; V-max, 86.8 [31.1] pmol/mg per minute), and multidrug resistance-associated protein 3 (K-m, 1.8 [0.3] mmol/L; V-max, 116 [15.9] pmol/mg per minute) but not for the apical sodium-dependent bile acid transporter and organic cation transporter 3. After the oral administration to the wild-type animals, Gd-EOB-DTPA was considerably absorbed from the small intestine (bioavailability, approximately 17%) and predominately eliminated via feces after intravenous dosing (approximately 96%). In the Mrp2-deficient rats, oral bioavailability increased to approximately 21% and Gd-EOB-DTPA was exclusively excreted into urine. Magnetic resonance enhancement of the liver was significantly prolonged in the Mrp2-deficient rats compared with the wild-type rats (mean [SD] area under the curve(0-90), 36.4 [8.5] vs 14.8 [10.3] arbitary units per minute; P = 0.003; time to maximum plasma concentration, 48.6 [23.8] vs 6.0 [3.1] minutes; P = 0.001).Conclusions The nonmetabolized Gd-EOB-DTPA may have some potentials to be used as a probe-contrast agent to evaluate transporter-mediated mechanisms along the enterohepatic absorption route for drugs by functional visualization in vivo.