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 gado linium chelate dimeglumine gadopentetate (Gd-DTPA, Magnevist(R), CAS 8 6050-77-3) yielded (4S) 4-(4-ethoxybenzyl)-3,6,9-tris (carboxylatom-et hyl)-3,6,9-triazaundecandioic acid, gadolinium complex, disodium salt (Gd-EOB-DTPA), a compound with a potential as a magnetic resonance con trast agent for liver mass screening Both in the rat and in the dog th e 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 correct ion for the difference in dose the plasma concentration-time profiles were not superimposable and the amounts excreted renally and fecally d iffered significantly (p < 0.05). Extrarenal elimination played an imp ortant role since fecal elimination (% of dose) was 73.4 +/- 5.6 in ra ts (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 (Cl(r)) were independent of dose and close to the value of the glomerular filtration rate (Cl(r) 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-D TPA can best be described by a capacity-limited transport process via the biliary route of elimi nation thus strongly resembling the pharmacokinetics of some biliary X -ray contrast media (iotroxic, iodipamic or iodoxamic acid) or the syn thetic 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).