Radiology · 2014
Advanced fibrosis: Correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver.
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Lagadec Matthieu, Doblas Sabrina, Giraudeau Céline, Ronot Maxime, Lambert Simon A, Fasseu Magali, Paradis Valérie, Moreau Richard, Pastor Catherine M, Vilgrain Valérie, Daire Jean-Luc, Van Beers Bernard E
Аннотация
PURPOSE: To compare the value of enhancement and pharmacokinetic parameters measured at dynamic gadoxetate-enhanced magnetic resonance (MR) imaging in determining hepatic organic anion transporter expression in control rats and rats with advanced liver fibrosis.
MATERIALS AND METHODS: Institutional animal review board approval was received before the study began. Advanced liver fibrosis was created in rats by means of carbon tetrachloride injections over an 8-week period. In 17 rats with liver fibrosis and eight control rats, dynamic gadoxetate-enhanced MR images of the liver were obtained during 1 hour after injection of 0.025 mmol gadoxetate per kilogram of body weight. Enhancement parameters (maximum enhancement [Emax], time to peak [Tmax], and elimination half-life) were measured on enhancement-versus-time curves, and pharmacokinetic parameters (hepatic extraction fraction [HEF] and mean residence time [MRT]) were obtained by means of deconvolution analysis of the concentration-versus-time curves in the liver and the portal vein. The parameters were correlated at simple and multiple regression analysis with the expression of the hepatic anion uptake transporter organic anion-transporting polypeptide 1A1 (Oatp1a1), the hepatobiliary transporter multidrug resistance-associated protein 2 (Mrp2), and the backflux transporter Mrp4, as determined with reverse transcription polymerase chain reaction.
RESULTS: In rats with advanced liver fibrosis, the Emax, Tmax, HEF, and MRT decreased significantly relative to those in control rats, whereas the elimination half-life increased significantly. The enhancement and pharmacokinetic parameters correlated significantly with the expression of the transporters at simple regression analysis. At multiple regression analysis, HEF was the only parameter that was significantly associated with the expression of Oatp1a1 and Mrp2 (P < .001, r = 0.74 and P < .001, r = 0.70, respectively).
CONCLUSION: The pharmacokinetic parameter HEF at dynamic gadoxetate-enhanced MR imaging is independently correlated with hepatic organic anion transporter expression.
MATERIALS AND METHODS: Institutional animal review board approval was received before the study began. Advanced liver fibrosis was created in rats by means of carbon tetrachloride injections over an 8-week period. In 17 rats with liver fibrosis and eight control rats, dynamic gadoxetate-enhanced MR images of the liver were obtained during 1 hour after injection of 0.025 mmol gadoxetate per kilogram of body weight. Enhancement parameters (maximum enhancement [Emax], time to peak [Tmax], and elimination half-life) were measured on enhancement-versus-time curves, and pharmacokinetic parameters (hepatic extraction fraction [HEF] and mean residence time [MRT]) were obtained by means of deconvolution analysis of the concentration-versus-time curves in the liver and the portal vein. The parameters were correlated at simple and multiple regression analysis with the expression of the hepatic anion uptake transporter organic anion-transporting polypeptide 1A1 (Oatp1a1), the hepatobiliary transporter multidrug resistance-associated protein 2 (Mrp2), and the backflux transporter Mrp4, as determined with reverse transcription polymerase chain reaction.
RESULTS: In rats with advanced liver fibrosis, the Emax, Tmax, HEF, and MRT decreased significantly relative to those in control rats, whereas the elimination half-life increased significantly. The enhancement and pharmacokinetic parameters correlated significantly with the expression of the transporters at simple regression analysis. At multiple regression analysis, HEF was the only parameter that was significantly associated with the expression of Oatp1a1 and Mrp2 (P < .001, r = 0.74 and P < .001, r = 0.70, respectively).
CONCLUSION: The pharmacokinetic parameter HEF at dynamic gadoxetate-enhanced MR imaging is independently correlated with hepatic organic anion transporter expression.