Efficacy of the iodine-free computed tomography liver contrast agent, Dy-EOB-DTPA, in comparison with a conventional iodinated agent in normal and in tumor-bearing rabbits.

RATIONALE AND OBJECTIVES: To investigate the efficacy of the new liver-specific x-ray contrast agent, Dy-EOB-DTPA, in rabbits with VX2 liver tumors by spiral computed tomography (CT) in comparison to iopromide. MATERIALS AND METHODS: The time course of liver enhancement was determined in five groups of two normal anesthetized rabbits, which received intravenous injections of Dy-EOB-DTPA before anesthesia at a dose of 0.5 mmol/kg. Fifteen, 30, 45, 60, and 90 minutes after administration spiral CT images were obtained and the attenuation in the livers were determined. A second group of ten rabbits with implanted VX2 tumors received in a random crossover design either Dy-EOB-DTPA at a dose of 0.5 mmol/kg or, 1 day later, iopromide at a dose of 600 mg iodine/kg. CT images were obtained 60 minutes after Dy-EOB-DTPA administration and both in the arterial and portal-venous phases after iopromide injection. Three radiologists evaluated the images. The rabbits were killed, and their livers were investigated histologically for liver tumors. RESULTS: In normal animals, 0.5 mmol/kg Dy-EOB-DTPA resulted in a liver enhancement of 30 HU during the whole observation period of 90 minutes. In tumor-bearing animals, histology revealed 14 implanted tumors of 3-20 mm diameter. Sixty-five percent of the tumors were below 10 mm. Dy-EOB-DTPA was able to detect 13 tumors (93%), iopromide 11 (79%) both in the arterial and in the portal-venous phase. The difference was statistically not significant. In plain CT, seven tumors (50%) were found (P < 0.01 vs iopromide and Dy-EOB-DTPA). One scar and two sites of necrosis were detected by each of the methods. CONCLUSION: Dy-EOB-DTPA injection at a dose of 0.5 mmol/kg resulted in a long-lasting detectability of 93% of all implanted tumors versus 79% found with iopromide.

Gd-EOB-DTPA and Yb-EOB-DTPA: two prototypic contrast media for CT detection of liver lesions in dogs.

PURPOSE: To characterize computed tomographic (CT) attenuation of iodine, gadolinium, and ytterbium in vitro and to study CT liver enhancement after administration of two prototypic hepatocyte-directed contrast media in dogs. MATERIALS AND METHODS: Samples with increasing concentrations of iodine, gadolinium, and ytterbium were measured for CT attenuation in a water phantom at tube voltages of 80, 120, and 137 kV. Three groups of five adult beagle dogs each received a 0.5 mmol/kg dose of either gadoxetic acid disodium (gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid [EOB-DTPA]) or Yb-EOB-DTPA as intravenous infusions or Yb-EOB-DTPA as an intravenous bolus injection. RESULTS: At 120 kV, in vitro CT attenuation of gadolinium and ytterbium exceeded that of iodine by 41% and 45%, respectively, when measured at equal mass concentrations (in milligrams per milliliter of saline). In dogs, CT liver enhancement values above the precontrast liver attenuation were 32.6 HU +/- 2.3, 31.4 HU +/- 1.1, and 33.4 HU +/- 5.2 after 0.5 mmol/kg Gd-EOB-DTPA or Yb-EOB-DTPA infusion or Yb-EOB-DTPA bolus, respectively. The values were not significantly different (P > .05) CONCLUSION: Both Gd-EOB-DTPA and Yb-EOB-DTPA provide excellent CT liver enhancement in dogs. CT liver enhancement is not significantly altered by either the absorbing element (gadolinium vs ytterbium) or the mode of application (infusion vs bolus).

Pharmacokinetics of the liver-specific contrast agent Gd-EOB-DTPA in relation to contrast-enhanced liver imaging in humans.

This study was performed to evaluate the effect of dose on the pharmacokinetics and efficacy of the gadolinium-based contrast medium gadoxetic acid, disodium, [gadolinium (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6, 9-triazaundecandioic acid-disodium salt] (Gd-EOB-DTPA) as a liver-specific hepatobiliary contrast medium for computed tomography. Pharmacokinetics in serum and the pattern of elimination were investigated in 18 healthy volunteers up to 6 days after a 10-minute infusion of 0.2 mmol, 0.35 mmol, and 0.5 mmol of gadolinium per kilogram of body weight. Pharmacokinetic behavior was compared with the compute tomographic attenuation data in the liver parenchyma after the same doses in patients. Urinary and fecal excretion accounted for approximately equal portions of the administered dose. The degree of renal elimination increased with increasing doses, whereas renal clearance and half-life from urine data were not affected by dose. Dose-normalized area under the concentration-time curve was significantly increased with increasing doses indicating saturation in liver uptake for the highest dose. This finding was in agreement with the measured net increase in liver attenuation by computed tomography. Hepatic disposition revealed slight saturation phenomena for the highest dose (0.5 mmol gadolinium/kg). Nevertheless, this dose resulted in sufficient uptake by human liver, allowing for computed tomographic imaging.

A prototype liver-specific contrast medium for CT: preclinical evaluation of gadoxetic acid disodium, or Gd-EOB-DTPA.

PURPOSE: The suitability of the hepatobiliary contrast medium gadoxetic acid disodium, or Gd-EOB-DTPA, for liver enhancement at computed tomography (CT) was studied. MATERIALS AND METHODS: CT attenuation levels at 120 kV were measured in samples of increasing concentrations of gadolinium (gadoxetic acid disodium) or iodine (iopromide) in aqueous solutions in vitro. In dogs, CT attenuation in the liver was measured up to 90 minutes after a single intravenous injection of 0.3, 0.5, and 0.7 mmol Gd/kg gadoxetic acid disodium (three dogs per dose group). In addition, three VX2 tumor-bearing rabbits were examined (0.7 mmol Gd/kg). RESULTS: In vitro, the CT attenuation of gadolinium is 40% higher than that of iodine if calculated per milligram of gadolinium and iodine, respectively. In dogs, the median net increase in liver enhancement was 25, 33, and 43 HU with a dose of 0.3, 0.5, and 0.7 mmol Gd/kg, respectively. The gallbladder and bile ducts became clearly visible. In rabbits, liver enhancement of 25 HU provided improved visualization of the unenhanced tumor. CONCLUSION: Because of the higher CT attenuation of gadolinium compared with iodine and because of its liver-specific uptake, gadoxetic acid disodium is a contrast medium that may improve diagnosis of pathologic liver conditions at CT.

[Electron-beam tomographic imaging of the coronary arteries: an experimental comparison between monomeric and dimeric x-ray contrast media]. / Elektronenstrahltomographische Darstellung der Koronararterien: Experimenteller Vergleich zwischen einem monomeren und einem dimeren Röntgenkontrastmittel.

PURPOSE: Comparison of a monomeric and a dimeric radiographic contrast medium in the visualisation of the coronary arteries via electron beam tomography (EBT). MATERIAL AND METHODS: In a total of 6 Göttingen minipigs the heart was examined by EBT (40 sections, ECG-triggering, 1.5 mm section thickness, 100 ms acquisition time) after injection of both iopamidol (monomer, 370 mg l/ml) and iotrolan (dimer, 320 mg l/ml) at a dose of 740 mg l/kg. Injection rate and scan delay were adjusted to heart rate and circulation time. RESULTS: The intravascular increase in density after intravenous injection of iotrolan was significantly higher and longer than after injection of iopamidol (> 300 HE: 28 +/- 4 versus 17 +/- 5 cardiac cycles; p < 0.05). Iotrolan attained a higher score in the visualisation of the coronary arteries in three-dimensional surface reconstructions (p < 0.05). CONCLUSION: The dimeric contrast medium iotrolan proved superior to the monomeric agent iopamidol for visualisation of the coronary arteries via EBT.

Ytterbium- and dysprosium-EOB-DTPA. A new prototype of liver-specific contrast agents for computed tomography.

RATIONALE AND OBJECTIVES: A series of studies was conducted to determine whether metal complexes of the EOB-DTPA type are useful as contrast agents for computed tomography (CT). METHODS: Metal complexes using EOB-DTPA as ligand were synthesized with lanthanide metal ions (lanthanum [La], cerium [Ce], praseodyme [Pr], gadolinium [Gd], dysprosium [Dy], ytterbium [Yb], and lutetium [Lu]) and with nonlanthanides (lead [Pb] and bismuth [Bi]). Complex stability was assessed by measuring binding to bone meal. The physicochemical parameters partition coefficient, osmolality, viscosity, and protein binding were determined in vitro. Tolerability was tested both in vitro (thromboplastin time, effect on erythrocytes) and in vivo (acute, neural, and cardiovascular toxicities). Biliary excretion and tissue distribution, especially liver, kidney, and bone concentrations, were measured in rats after intravenous doses of 0.5 mmol/kg. Imaging performance using CT was investigated in vitro in a phantom model and, for Gd-EOB-DTPA, in vivo by injecting doses of 0.5 mmol/kg into healthy or tumor-bearing rats and rabbits. RESULTS: The kinetic stability of M-EOB-DTPA complexes differed widely. Nonlanthanide metals, especially Pb-EOB-DTPA, provided less stable complexes than lanthanides with an optimum of stability for the metals Gd, Dy, Yb, and Lu. Tolerability was good for all compounds, best results were obtained for Gd and Yb. Concentrations in rat liver after administration of Gd-EOB-DTPA, 0.5 mmol/kg intravenous, were approximately 1 mumol/g, resulting in CT enhancement of 16 Hounsfield units (HU). Tumor tissue was not enhanced. In rabbits, at the same dose level 30 HU was found. CONCLUSIONS: Metal complexes of the EOB-DTPA type, especially those of Gd and Yb seem to be useful as iodine-free liver-specific contrast agents for CT.

Cardiac and hemodynamic tolerability of iodinated contrast media in the anesthetized rat.

RATIONALE AND OBJECTIVES: The study was designed to compare the hemodynamic effects of 11 iodinated contrast media (CM), including ionic (diatrizoate, ioxaglate), nonionic monomeric (iohexol, iopromide, iopamidol, iopentol, ioversol, iomeprol, ZK 139129), and nonionic dimeric (iotrolan, iodixanol) compounds. METHODS: Following left ventricular bolus injection of 1.2 g I/kg body weight in anesthetized rats, cardiohemodynamic parameters were measured. RESULTS: Compared with the control group, except for blood pressure (BP), all CM showed a similar response regarding the direction of the cardiohemodynamic changes after CM injection. A biphasic change in BP was observed for diatrizoate and iodixanol, whereas all other CM showed a transient increase in BP being most pronounced for ioxaglate. No arrhythmias were detected. The increase in LVEDP was lowest for the isotonic dimeric CM iotrolan and iodixanol. CONCLUSIONS: Only mild transient side effects were observed. Low osmolar, especially isotonic, dimeric CM show a clear benefit regarding cardiovascular side effects.

Evaluation of gadobutrol in a rabbit model as a new lanthanide contrast agent for computed tomography.

RATIONALE AND OBJECTIVES: The efficacy of the neutral lanthanide contrast agent gadobutrol was compared to that of the iodinated contrast agent iopromide in rabbits. METHODS: The computed tomography (CT) attenuation of increasing concentrations of gadolinium (Gd) (gadobutrol) and iodine (I) (iopromide) was measured in Hounsfield units (HU) in aqueous solution at 80, 120, and 137 kV. The peak enhancement (net increase in CT attenuation compared with baseline) and the time-enhancement product in the aorta and in the renal parenchyma of the outer and inner cortex were measured in rabbits over a 5-minute period after the animals were given single intravenous injections of 0.7, 1.0, and 1.5 mmol Gd/kg of gadobutrol and 1.0 and 2.4 mmol I/kg of iopromide. RESULTS: In vitro, the CT attenuation of gadolinium was 40% higher than that of iodine at equivalent mass concentrations (120 kV). The mean peak enhancements in the aorta after the injections of 0.7, 1.0, and 1.5 mmol Gd/kg and 1.0 and 2.4 mmol I/kg were 216, 313, 591, 224, and 498 HU, respectively. In addition, a 30-second injection of the high dose of gadobutrol resulted in an attenuation profile that was suitable for a three-dimensional reconstruction of the aorta and the renal vasculature. CONCLUSIONS: Because of the higher CT attenuation of gadolinium compared with that of iodine, the neutral macrocyclic chelate gadobutrol is a more effective contrast agent than iopromide for CT at lower doses of the imaging atom.

Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging.

The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 l/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the range of other low osmolality contrast media for MRI. Only very little interaction with biologically relevant molecules was suggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imaging experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.

Liver contrast enhancement in primates using iopromide liposomes.

RATIONALE AND OBJECTIVES: We studied the feasibility of using iodinated liposomes as computed tomography (CT) liver contrast agents in nonhuman primates. METHODS: Iopromide-containing liposomes were investigated as reticuloendothelial (RES) contrast agents for CT scanning of the liver in normal adult baboons. For intravenous (i.v.) injection, liposomes were resuspended in mannitol solution, filtered under sterile conditions, and injected i.v. at doses of 200 and 400 mg l/kg to each of five anesthetized adult baboons. RESULTS: Animals tolerated the injections without measurable electrocardiographic changes and recovered uneventfully from anesthesia. Sequential CT scans of the baboons' upper abdomen acquired up to 60 min postinjection showed persistent enhancement of the liver 10-60 min after injection. Maximum enhancement levels were 36 and 61 delta Hounsfield units (delta H) after the 200- and 400-mg/kg doses, respectively. The mean time to plateau enhancement was 20 min with the 200-mg/kg dose and 10 min with the 400-mg/kg dose. The greatest splenic enhancements were 181 and 301 delta H after the 200- and 400-mg/kg doses, respectively. CONCLUSION: Iopromide liposomes are effective as RES contrast agents in primates.

Pharmacokinetics of iopromide liposomes in rabbits.

PURPOSE: The dose-proportionality of pharmacokinetics of an iodinated contrast medium, iopromide, encapsulated into liposomes was investigated. METHODS: Following single intravenous administration of 150 mg iodine/kg (potential diagnostic dose) and a five-fold higher dose in rabbits the pattern of elimination was studied until 7 d and the blood concentrations were monitored up to 72 h after administration. The iodine concentration in the liver was calculated on the basis of the blood concentration and related to the concentration measured in the rabbit liver. RESULTS: The dose-normalized blood concentration-time profiles of the encapsulated iodine were not superimposable. Contrary to the low dose a steady-state concentration of 2.8 mg iodine/mL was observed in blood for 60 min after the high dose administration indicating a saturation of the liposomal liver uptake. For both doses the elimination of iodine occurred predominantly via the kidneys and was complete 7 d after administration. The dose-normalized amounts of iodine excreted with the urine were similar for both dose groups. From the blood data it was calculated that doses up to about 300 mg iodine/kg should result in a dose-proportional increase of liposomal liver uptake before saturation occurs. This was confirmed by the measured iodine liver concentrations after increasing the doses stepwise from 150 to 750 mg iodine/kg. CONCLUSIONS: In rabbits for the dose range 150 to 750 mg iodine/kg iopromide liposomes reveal dose-dependent pharmacokinetics due to a saturation in liver uptake which occurs for doses of 300 mg iodine/kg corresponding to 300 mg lipid/kg onwards.

Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers.

RATIONALE AND OBJECTIVES: Gadobutrol is a new gadolinium-based hydrophilic and neutral macrocyclic contrast medium for magnetic resonance imaging. In this article, the authors report on the first application of gadobutrol in humans, up to a dose of 0.5 mmol/kg. METHODS: Gadobutrol was investigated after single intravenous administration in two phase-1 studies testing low (0.5 mol/L) and high concentrations (1 mol/L) in healthy, male volunteers using a double-blind, randomized, placebo-controlled study with n = 55 for the low concentration (0.04, 0.1, 0.2, 0.3, and 0.4 mmol/kg body weight), followed by n = 36 for the high concentration (0.3, 0.4, and 0.5 mmol/kg body weight). Vital signs and laboratory parameters were measured for all dose groups investigated, whereas for the calculation of the pharmacokinetic parameters, the dose groups 0.04, 0.1, and 0.4 mmol/kg body weight were selected. RESULTS: Gadobutrol was well tolerated up to doses of 0.5 mmol/kg, and no relevant changes in vital signs and laboratory parameters occurred. The terminal disposition half-life of gadobutrol in plasma was approximately 1.5 hours. Total clearance approximated renal clearance and approximated the value of 120 mL/min, indicating glomerular filtration as the main pathway of elimination. The steady-state volume of distribution indicated predominantly extracellular distribution of gadobutrol. No metabolites were detected. The renal excretion rate was linear over the large dose range tested, indicating dose-proportionate, first-order kinetics of gadobutrol. CONCLUSION: Single intravenous administration of gadobutrol was well tolerated up to the dose level of 0.5 mmol/kg body weight. These factors suggest that gadobutrol will be a safe magnetic resonance imaging contrast agent.

Dose proportionality of iopromide pharmacokinetics and tolerability after i.v. injection in healthy volunteers.

Twelve healthy male volunteers participated in a single-blind, randomised, placebo-controlled cross-over study of i.v. iopromide in doses of 15 g iodine or 80 g iodine infused over a period of 15 min. The volunteers were observed for three days during which time blood samples, urine and faeces were collected. The terminal disposition phase half-life of iopromide was 2 h and 1.9 h, and the total clearance was 110 and 103 ml.min-1 at the lower and at the higher dose levels, respectively. The steady state volume of distribution was 16 and 17 l, indicating predominantly extracellular distribution of iopromide. Statistical analysis (one-sided t-test) showed that all the target parameters (AUC, half-life and urinary excretion) were equivalent at both dose levels, indicating dose proportionate, first order kinetics of iopromide over the large dose range tested. Iopromide was well tolerated after both doses.

Characterization of iopromide liposomes.

RATIONALE AND OBJECTIVES: Iopromide-carrying liposomes were prepared and were characterized pharmaceutically and biologically. METHODS: The liposomes were prepared by the ethanol evaporation method and were characterized by quasi-elastic light scattering (size) and equilibrium dialysis (encapsulation efficiency and stability). Acute and subchronic toxicity was tested in mice and/or rats and cardiovascular tolerance in rabbits. Pharmacokinetic parameters were determined in rats. Computed tomography (CT) imaging efficiency was obtained from rat and rabbit studies. RESULTS: The mean diameter was 0.5 +/- 0.1 micron and the encapsulation efficiency ranged between 30% and 40%. The liposomes were stable in human and rabbit plasma for approximately 24 hours. The LD50 in mouse and rat was approximately 3 g iodine/kg. In a subchronic toxicity study in rats with six doses of 1 g iodine/kg given every three days, no adverse effects were observed. The pharmacokinetics in rats were dose-dependent. Increasing the dose resulted in lower total clearance, and longer terminal half-life. Elimination of iodine was complete and the main route of excretion was via the kidneys. A clinically relevant computed tomography enhancement of the liver was reached after approximately 200 mg iodine/kg in rats and 150 mg iodine/kg in rabbits. CONCLUSIONS: The iopromide-carrying liposomes were well tolerated in animal studies and seemed to be suitable for the imaging of the liver.

Pharmaceutical properties, biodistribution, and imaging characteristics of manganese-mesoporphyrin. A potential hepatobiliary contrast agent for magnetic resonance imaging.

OBJECTIVES: Manganese (III) mesoporphyrin (Mn-mesoporphyrin) was investigated for its pharmaceutical properties and magnetic resonance imaging characteristics as a potential hepatobiliary contrast agent. METHODS: Solubility, partition coefficient, plasma binding, proton relaxation enhancement, biodistribution, biliary excretion, liver extraction ratio, and liver enhancement were measured in various in-vitro and in-vivo systems. RESULTS: Mn-mesoporphyrin was soluble and stable at moderate alkaline pH in phosphate buffer. The octanol/water coefficient was 25.98, and the compound was highly protein bound. R1 for water and plasma were 1.94 and 2.35 L/mmol sec, respectively. R1 in liver was calculated to be 15.72 L/mmol sec. Biodistribution studies in rats and mice confirmed hepatotrophic properties and biliary excretion was 65% over 24 hours. First pass liver uptake was 15%. Magnetic resonance imaging studies showed persistent liver enhancement at 0.05 mmol/kg. CONCLUSION: Mn-mesoporphyrin is a lipophilic compound that shows potential as a hepatobiliary magnetic resonance contrast agent.

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.

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).