The Use of Magnetic Resonance Methods in Translational Cardiovascular Research

From, Arthur H. L.; Uğurbil, Kâmil

doi:10.1007/s12265-008-9084-3

Cited by 1 publication

(1 citation statement)

References 61 publications

(44 reference statements)

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“…To qualify this biomarker for use in drug development, further work needs to be conducted to explore effect size, robustness and timing with a broad range of drugs that alter transporter function and induce adaptation or DILI to understand the link between inhibition of hepatobiliary transporters in preclinical studies and the development of DILI in the clinic. MRI is directly translatable between animal studies and the clinic [ 49 ], and gadoxetate is a contrast agent approved for IV use to detect and characterize focal liver lesions in patients. Gadoxetate DCE-MRI detects changes in transporter activity due to polymorphisms in healthy subjects [ 50 ], and can predict hyperbilirubinemia during treatment of chronic hepatitis C patients [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function

Karageorgis¹,

Lenhard²,

Yerby³

et al. 2018

PLoS ONE

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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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Section: Discussionmentioning

confidence: 99%