Hepatic Kinetics and Magnetic Resonance Imaging of Gadolinium-EOB-DTPA in Dogs

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Abstract
RATIONALE AND OBJECTIVES To measure the hepatic uptake and biliary elimination kinetics of gadolinium (Gd)-EOB-DTPA in dogs. METHOD Two groups of four beagles each were anesthetized and given an intravenous bolus of 25 μmol/kg or 250 μmol/kg of Gd-EOB-DTPA. Blood, hepatic bile, and urine were collected over 140 minutes, and liver samples were obtained immediately after the dogs were killed. Conventional T1-weighted spin echo sequences of the liver were performed on a 1.5-Tesla (T) magnetic resonance imager during sampling. A ninth beagle received a bolus of 25 μmol/kg followed 140 minutes later with a bolus of 250 μmol/kg of Gd-EOB-DTPA. Wedge liver biopsies were obtained for Gd estimation at various times after dosing, and Gd concentration was measured by inductively coupled plasma atomic emission spectroscopy. RESULTS The plasma concentration of Gd-EOB-DTPA decreased in a biexponential manner with half-lives of approximately 4 minutes and 60 minutes for the distribution and elimination phase independent of the dose given. Gadolinium bile concentration reached peak values between 80 and 140 minutes: 6.3 ± 1.6 mmol/L for the low dose (LD) and 11.6 ± 2.8 mmol/L for the high dose (HD). Bile Gd output was 62.0 ± 8.8 (LD) and 78.3 ± 30.2 (HD) nmol/minute·kg 50 to 80 minutes after injection. Gadolinium-EOB-DTPA was excreted by the biliary route to 24.8 ± 2.6 (LD) and 3.6 ± 1.2 (HD) percent of the dose within 140 minutes. Liver Gd concentration was 0.43 ± 0.14 (LD) and 4.3 ± 0.5 (HD) mmol/kg liver tissue at the conclusion of the studies. Calculated concentrations in the hepatocyte were 60 (LD) and 15 (HD) times higher than in plasma at 25 minutes after dosing. Whereas the low dose exhibited excellent contrast enhancement for the whole period, the high dose displayed a biphasic signal enhancement with a decreasing signal caused by the too-high hepatic gadolinium accumulation. CONCLUSIONS Transport of the Gd-EOB-DTPA into the hepatocyte exceeded elimination from hepatocyte to bile. The high dose defined a biliary transport maximum for Gd-EOB-DTPA of 78.3 ± 30.2 nmol/minute·kg. The liver accumulation results from fast transport into the hepatocyte and rate-limited slower transport from hepatocyte to bile. The accumulation occurs against a strong concentration gradient, suggesting energy-dependent active transport into the hepatocyte.