Abstract
ObjectiveThe objective of this study was to use noninvasive dynamic contrast-enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers.Materials and MethodsTen healthy volunteers (age range, 18–29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast-enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time.ResultsEight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 ± 0.05 and 0.017 ± 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 ± 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: ±0.02/min, kef: ±0.004/min) was lower compared with the individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes.ConclusionsThis is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions.
Highlights
MethodsTracer Kinetic ModelThe model presented in this article (Fig. 1) is a dual-input2-compartmental uptake and efflux model, an extension of the uptake model of Sourbron et al,[24] that describes the pharmacokinetic properties of gadoxetate in the liver for a prolonged acquisition
The results highlight that dynamic contrast-enhanced magnetic resonance imaging (MRI) with gadoxetate can provide novel quantitative insights into liver function and may prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions
The results demonstrated that including the uptake rate parameter for the hepatocytes provided a better fit of the time series compared with the 1-compartmental model; the variability of the uptake rate estimates highlighted the need for more data to establish the reproducibility of the techniques
Summary
Tracer Kinetic ModelThe model presented in this article (Fig. 1) is a dual-input2-compartmental uptake and efflux model, an extension of the uptake model of Sourbron et al,[24] that describes the pharmacokinetic properties of gadoxetate in the liver for a prolonged acquisition. The model assumes that the liver parenchyma comprises (1) the extracellular space, which consists of the vascular (ie, plasma) and interstitial space, vp and ve, respectively, and (2) the intracellular space vi (ie, hepatocytes). A unidirectional linear efflux of contrast agent from the intracellular space to the bile canaliculi with a transfer rate kef was assumed. Because the volume of the bile canaliculi is extremely small compared with the overall extracellular and intracellular volumes, its contribution to the measured tissue concentration was assumed to be negligible; bile is continuously carried away from the liver through the hepatic bile ducts toward the common bile duct.[33,34] The model is defined in Equation 1
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