Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid

Jia Jia, Dorothee Puls, Stefan Oswald, Gabriele Jedlitschky, Jens P Kühn, Werner Weitschies, Norbert Hosten, Werner Siegmund, Markus Keiser
Investigative Radiology 2014, 49 (2): 78-86

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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"