Modeling Gadoxetate Liver Uptake and Efflux Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging Enables Preclinical Quantification of Transporter Drug-Drug Interactions.

OBJECTIVES: The aim of this study was to model the in vivo transporter-mediated uptake and efflux of the hepatobiliary contrast agent gadoxetate in the liver. The efficacy of the proposed technique was assessed for its ability to provide quantitative insights into drug-drug interactions (DDIs), using rifampicin as inhibitor. MATERIALS AND METHODS: Three groups of C57 mice were scanned twice with a dynamic gadoxetate-enhanced magnetic resonance imaging protocol, using a 3-dimensional spoiled gradient-echo sequence for approximately 72 minutes. Before the second magnetic resonance imaging session, 2 of the groups received a rifampicin dose of 20 (n = 7) or 40 (n = 7) mg/kg, respectively. Data from regions of interest in the liver were analyzed using 2 simplifications of a 2-compartment uptake and efflux model to provide estimates for the gadoxetate uptake rate (ki) into the hepatocytes and its efflux rate (kef) into the bile. Both models were assessed for goodness-of-fit in the group without rifampicin (n = 9), and the appropriate model was selected for assessing the ability to monitor DDIs in vivo. RESULTS: Seven of 9 mice from the group without rifampicin were assessed for model implementation and reproducibility. A simple 3 parameter model (ki, kef, and extracellular space, vecs) adequately described the observed liver concentration time series with mean ki = 0.47 ± 0.11 min and mean kef = 0.039 ± 0.016 min. Visually, the area under the liver concentration time profile was reduced for the groups receiving rifampicin. Furthermore, tracer kinetic modeling demonstrated a significant dose-dependent decrease in the uptake (5.9- and 17.3-fold decrease for 20 mg/kg and 40 mg/kg, respectively) and efflux rates (2.2- and 7.9-fold decrease) compared with the first scan for each group. CONCLUSIONS: This study presents the first in vivo implementation of a 2-compartment uptake and efflux model to monitor DDIs at the transporter-protein level, using the clinically relevant organic anion transporting polypeptide inhibitor rifampicin. The technique has the potential to be a novel alternative to other methods, allowing real-time changes in transporter DDIs to be measured directly in vivo.

Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging: Monitoring Transporter-Mediated Processes in Healthy Volunteers.

OBJECTIVE: The 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 METHODS: Ten 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. RESULTS: Eight 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. CONCLUSIONS: This 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.

Pharmacokinetic/pharmacodynamic modelling of the EEG effects of opioids: the role of complex biophase distribution kinetics.

The objective of this investigation is to characterize the role of complex biophase distribution kinetics in the pharmacokinetic-pharmacodynamic correlation of a wide range of opioids. Following intravenous infusion of morphine, alfentanil, fentanyl, sufentanil, butorphanol and nalbuphine the time course of the EEG effect was determined in conjunction with blood concentrations. Different biophase distribution models were tested for their ability to describe hysteresis between blood concentration and effect. In addition, membrane transport characteristics of the opioids were investigated in vitro, using MDCK:MDR1 cells and in silico with QSAR analysis. For morphine, hysteresis was best described by an extended-catenary biophase distribution model with different values for k1e and keo of 0.038+/-0.003 and 0.043+/-0.003 min(-1), respectively. For the other opioids hysteresis was best described by a one-compartment biophase distribution model with identical values for k1e and keo. Between the different opioids, the values of k1e ranged from 0.04 to 0.47 min(-1). The correlation between concentration and EEG effect was successfully described by the sigmoidal Emax pharmacodynamic model. Between opioids significant differences in potency (EC50 range 1.2-451 ng/ml) and intrinsic activity (alpha range 18-109 microV) were observed. A statistically significant correlation was observed between the values of the in vivo k1e and the apparent passive permeability as determined in vitro in MDCK:MDR1 monolayers. It can be concluded that unlike other opioids, only morphine displays complex biophase distribution kinetics, which can be explained by its relatively low passive permeability and the interaction with active transporters at the blood-brain barrier.