Pharmacokinetics in rats, dogs and monkeys 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 dimeglumine gadopentetate (Gd-DTPA, Magnevist, CAS 86050-77-3) yielded (4S) 4-(4-ethoxybenzyl)-3,6,9-tris (carboxylatomethyl)-3,6,9-triazaundecandioic acid, gadolinium complex, disodium salt (Gd-EOB-DTPA), a compound with a potential as a magnetic resonance contrast agent for liver mass screening. Both in the rat and in the dog the pharmacokinetics of Gd-EOB-DTPA were nonlinear in the dose range of 0.05-0.5 mmol/kg (rat) and 0.03-0.25 mmol/kg (dog) since after correction for the difference in dose the plasma concentration-time profiles were not superimposable and the amounts excreted renally and fecally differed significantly (p < 0.05). Extrarenal elimination played an important role since fecal elimination (% of dose) was 73.4 +/- 5.6 in rats (0.05 mmol/kg), 70.1 +/- 4.0 in dogs (0.03 mmol/kg) and 32.1 +/- 6.4 in monkeys (0.25 mmol/kg). However, in all species investigated, the values of renal clearance (Clr) were independent of dose and close to the value of the glomerular filtration rate (Clr in ml/min.kg: 10.4 +/- 3.5 in rats; 3.88 +/- 0.8 in dogs; 1.01 +/- 0.3 in monkeys). Therefore, the pharmacokinetics of Gd-EOB-DTPA can best be described by a capacity-limited transport process via the biliary route of elimination thus strongly resembling the pharmacokinetics of some biliary X-ray contrast media (iotroxic, iodipamic or idoxamic acid) or the synthetic dyes (indocyanine green). However, contrary to the latter agents the plasma binding (%) of Gd-EOB-DTPA was low in all species (10.3 +/- 1.4 in rats: 10.0 +/- 1.3 in dogs; 17.5 +/- 1.0 in monkeys).