A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function.
A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function.
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DOI：
10.1371/journal.pone.0197213
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Hockings PD
中科院分区：
文献类型：
--
作者：
Karageorgis A;Lenhard SC;Yerby B;Forsgren MF;Liachenko S;Johansson E;Pilling MA;Peterson RA;Yang X;Williams DP;Ungersma SE;Morgan RE;Brouwer KLR;Jucker BM;Hockings PD
药物性肝损伤（DILI）是急性肝衰竭和肝移植的主要原因。DILI可能是肝胆转运受损的结果，伴随着胆汁形成、流动的改变，以及随后的胆汁淤积。我们使用gadoxetate动态对比增强磁共振成像（DCE-MRI），结合药代动力学建模，测量大鼠体内肝胆转运蛋白的功能。通过在四个不同的临床前成像中心评估抗生素利福平临床剂量的效果，测试了该方法的敏感性和稳健性。各中心载药组的gadoxetate平均摄取速率常数为39.3 +/- 3.4 s-1 (n = 23)，利福平组为11.7 +/- 1.3 s-1 （n = 20）。药物组的平均加多赛特流出速率常数为1.53 +/- 0.08 s-1 (n = 23)，利福平治疗组的平均流出速率常数为0.94 +/- 0.08 s-1 （n = 20）。在所有中心，利福平的临床剂量均显著抑制了加多赛特的摄取和排泄转运体，并且该治疗组效应的大小在各中心是一致的。Gadoxetate是一种临床批准的MRI造影剂，因此这种方法很容易转移到临床。结论：在确定肝毒性生物标志物之前，gadoxetate摄取和排泄速率常数是检测大鼠体内肝胆转运蛋白功能早期变化的敏感和可靠的生物标志物。
Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic. Conclusion: Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.
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