OBJECTIVES: The objectives of the study were to measure the pharmacokinetics and liver enhancement of gadoxetate (gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid [Gd-EOB-DTPA], Eovist, Primovist) after oral and intravenous administration in wild-type and (multidrug resistance-associated protein 2) Mrp2-deficient rats and to evaluate the in vitro transport of the contrast agent via intestinal and hepatic transporter proteins. MATERIALS AND METHODS: Gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging and pharmacokinetics of Gd-EOB-DTPA after intravenous and oral administration were evaluated in wild-type and Mrp2-deficient rats using T1-weighted magnetic resonance imaging and a validated liquid chromatography-mass spectrometry method, respectively. Cellular uptake of Gd-EOB-DTPA was measured in stably transfected human embrionic kidney 293-cells expressing oragnic anion-transporting polypeptide 1A2 or organic cation transporter 3 and Madin Darby canine kidney 2-cells expressing apical sodium dependent bile acid transporter. The affinity to MRP2 and multidrug resistance-associated protein 3 was measured using inside-out vesicles. RESULTS: In vitro, Gd-EOB-DTPA was demonstrated to be a substrate for OATP1A2 (mean [SD] of the Michaelis-Menten constant [K(m)], 1.0 [0.4] mmol/L; mean [SD] of the maximal uptake rate [V(max)], 101.3 [21.1] pmol/mg per minute), MRP2 (K(m), 1.0 [0.5] mmol/L; V(max), 86.8 [31.1] pmol/mg per minute), and multidrug resistance-associated protein 3 (K(m), 1.8 [0.3] mmol/L; V(max), 116 [15.9] pmol/mg per minute) but not for the apical sodium-dependent bile acid transporter and organic cation transporter 3. After the oral administration to the wild-type animals, Gd-EOB-DTPA was considerably absorbed from the small intestine (bioavailability, approximately 17%) and predominately eliminated via feces after intravenous dosing (approximately 96%). In the Mrp2-deficient rats, oral bioavailability increased to approximately 21% and Gd-EOB-DTPA was exclusively excreted into urine. Magnetic resonance enhancement of the liver was significantly prolonged in the Mrp2-deficient rats compared with the wild-type rats (mean [SD] area under the curve0-90, 36.4 [8.5] vs 14.8 [10.3] arbitary units per minute; P = 0.003; time to maximum plasma concentration, 48.6 [23.8] vs 6.0 [3.1] minutes; P = 0.001). CONCLUSIONS: The nonmetabolized Gd-EOB-DTPA may have some potentials to be used as a probe-contrast agent to evaluate transporter-mediated mechanisms along the enterohepatic absorption route for drugs by functional visualization in vivo.
OBJECTIVES: The objectives of the study were to measure the pharmacokinetics and liver enhancement of gadoxetate (gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid [Gd-EOB-DTPA], Eovist, Primovist) after oral and intravenous administration in wild-type and (multidrug resistance-associated protein 2) Mrp2-deficient rats and to evaluate the in vitro transport of the contrast agent via intestinal and hepatic transporter proteins. MATERIALS AND METHODS: Gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging and pharmacokinetics of Gd-EOB-DTPA after intravenous and oral administration were evaluated in wild-type and Mrp2-deficient rats using T1-weighted magnetic resonance imaging and a validated liquid chromatography-mass spectrometry method, respectively. Cellular uptake of Gd-EOB-DTPA was measured in stably transfected human embrionic kidney 293-cells expressing oragnic anion-transporting polypeptide 1A2 or organic cation transporter 3 and Madin Darby canine kidney 2-cells expressing apical sodium dependent bile acid transporter. The affinity to MRP2 and multidrug resistance-associated protein 3 was measured using inside-out vesicles. RESULTS: In vitro, Gd-EOB-DTPA was demonstrated to be a substrate for OATP1A2 (mean [SD] of the Michaelis-Menten constant [K(m)], 1.0 [0.4] mmol/L; mean [SD] of the maximal uptake rate [V(max)], 101.3 [21.1] pmol/mg per minute), MRP2 (K(m), 1.0 [0.5] mmol/L; V(max), 86.8 [31.1] pmol/mg per minute), and multidrug resistance-associated protein 3 (K(m), 1.8 [0.3] mmol/L; V(max), 116 [15.9] pmol/mg per minute) but not for the apical sodium-dependent bile acid transporter and organic cation transporter 3. After the oral administration to the wild-type animals, Gd-EOB-DTPA was considerably absorbed from the small intestine (bioavailability, approximately 17%) and predominately eliminated via feces after intravenous dosing (approximately 96%). In the Mrp2-deficient rats, oral bioavailability increased to approximately 21% and Gd-EOB-DTPA was exclusively excreted into urine. Magnetic resonance enhancement of the liver was significantly prolonged in the Mrp2-deficient rats compared with the wild-type rats (mean [SD] area under the curve0-90, 36.4 [8.5] vs 14.8 [10.3] arbitary units per minute; P = 0.003; time to maximum plasma concentration, 48.6 [23.8] vs 6.0 [3.1] minutes; P = 0.001). CONCLUSIONS: The nonmetabolized Gd-EOB-DTPA may have some potentials to be used as a probe-contrast agent to evaluate transporter-mediated mechanisms along the enterohepatic absorption route for drugs by functional visualization in vivo.
Authors: Sarah Billington; Adrian S Ray; Laurent Salphati; Guangqing Xiao; Xiaoyan Chu; W Griffith Humphreys; Mingxiang Liao; Caroline A Lee; Anita Mathias; Cornelis E C A Hop; Christopher Rowbottom; Raymond Evers; Yurong Lai; Edward J Kelly; Bhagwat Prasad; Jashvant D Unadkat Journal: Drug Metab Dispos Date: 2017-11-14 Impact factor: 3.922
Authors: Jean-Luc Daire; Benjamin Leporq; Valérie Vilgrain; Bernard E Van Beers; Sabine Schmidt; Catherine M Pastor Journal: Eur J Drug Metab Pharmacokinet Date: 2017-08 Impact factor: 2.441
Authors: Guido M Kukuk; Stephanie G Schaefer; Rolf Fimmers; Dariusch R Hadizadeh; Samer Ezziddin; Ulrich Spengler; Hans H Schild; Winfried A Willinek Journal: Eur Radiol Date: 2014-07-17 Impact factor: 5.315