BILIARY-EXCRETION AND PHARMACOKINETICS OF A GADOLINIUM CHELATE USED AS A LIVER-SPECIFIC CONTRAST AGENT FOR MAGNETIC-RESONANCE-IMAGING IN THE RAT

The introduction of a lipophilic moiety into the gadolinium chelate Gd -DTPA (dimeglumine gadopentetate, Magnevist) yielded Gd-EOB-DTPA (shor t form), which has potential as a magnetic resonance contrast agent fo r liver mass screening. The pharmacokinetics of Gd-EOB-DTPA in rats is nonlinear because after correction for the 1 0-fold difference in dos e, the area under the curve of plasma concentration versus time from t ime zero to infinity after single intravenous application of two diffe rent doses were not superimposable, and the amounts excreted renally a nd extrarenally differed significantly. However, for both dose groups tested, the values of renal clearance (9.96 and 11.1 mL/min - kg, resp ectively) were close to the value of glomerular filtration in the rat. Michaelis-Menten kinetics in the extrarenal elimination was therefore considered as the rate-limiting process of Gd-EOB-DTPA, the binding t o plasma protein of which is small (10.3 +/- 1.4%). Thus, biliary elim ination was significantly inhibited by the intravenous coadministratio n of sulfobromophthalein (a decrease from 39.5 +/- 3.17 to 30.7 +/- 5. 30% of the dose was observed from 0 to 90 min postinoculation under co administration of the inhibitor), whereas tauroglycocholate revealed n o effect, indicating the involvement of the so-called organic anion pl asma membrane transport system for the hepatic uptake. The transport o f Gd-EOB-DTPA from the cytoplasm to the bile is mainly determined by t he capacity of the transport protein glutathione-S-transferase as demo nstrated by in vitro binding studies. A hepatobiliary transport maximu m of 9.2 mumol/min . kg was evaluated by infusion studies. No metaboli tes were detected either in the bile or in the urine, and enterohepati c circulation can be excluded.