Nonlinear pharmacokinetic modeling of a gadolinium chelate used as a liver-specific contrast agent for magnetic resonance imaging.

The introduction of the lipophilic moiety, ethoxybenzyl, into the gadolinium chelate gadopentate dimeglumine (Gd-DTPA, Magnevist, CAS 86050-77-3) yielded gadolinium-(4S)4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl+ ++)-3,6,9- triazaundecandioic acid, disodium salt (Gd-EOB-DTPA) a compound with a potential as a magnetic resonance contrast agent for liver mass screening. After intravenous administration in rats (0.05 and 0.5 mmol/kg), dogs (0.03 and 0.25 mmol/kg) and monkeys (0.25 mmol/kg) Gd-EOB-DTPA was only slightly bound to plasma proteins and underwent both renal and extrarenal elimination. The pharmacokinetic behaviour in rats, dogs and monkeys could be well described by disposition of the compound in the central and peripheral compartment with elimination occurring from the central compartment, allowing for Michaelis-Menten kinetics for the extrarenal (biliary) route of elimination and linear kinetics for the renal route of elimination. Nonlinear pharmacokinetic modeling yielded Vmax values (mumol/min.kg) of 4.34 +/- 0.65 in rats, 2.40 +/- 0.98 in dogs and 0.810 +/- 0.66 in monkeys. In the rat the Vmax value obtained by nonlinear modeling was in good agreement with the biliary transport maximum measured after intravenous bolus injection of increasing dose levels.