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


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.
From the *Department of Clinical Pharmacology, Center of Drug Absorption and Transport; †Department of Diagnostic Radiology and Neuroradiology, University Medicine of Greifswald; and Departments of ‡Pharmacology and §Pharmacy of the Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany.
Jia
J
Jia
Dorothee
D
Puls
Stefan
S
Oswald
Gabriele
G
Jedlitschky
Jens P
JP
Kühn
Werner
W
Weitschies
Norbert
N
Hosten
Werner
W
Siegmund
Markus
M
Keiser
D000818:Animals; D003287:Contrast Media / Q000493:pharmacokinetics; D004285:Dogs; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism*; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution
D003287:Contrast Media; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA