How does a drug-coated balloon work? Overview about coating technologies and their impact.

BACKGROUND: According to current understanding the drug-coated balloon carries a sufficient dose of an effective antineoplastic agent, i.e. paclitaxel, to the target lesion. METHODS: Literature review and report on experimental studies simulating the access of coated balloons to the treatment site and studies in pigs. RESULTS: The drug adheres to the balloon membrane and is partially hidden below the folds which are wrapped around the shaft. Upon inflation solid paclitaxel particles are pushed into the vessel wall. Premature loss of paclitaxel and transfer to the vessel wall is controlled by the formulation including an inactive additive. Particles in the tissue dissolve slowly resulting in a terminal half-life of almost 2 months. Premature loss of the drug, dissolution, elimination, efficacy and tolerance are limited by the very low solubility of paclitaxel. From exemplary DCB approximately 10% of drug is lost before the target lesion is reached, 5-20% is transferred into the vessel wall and 10% remain on the balloon after withdrawal. The difference is distributed in the general circulation. Inhibition of neointimal proliferation in animal models is reliable and as persistent as with drug-eluting stents. Histology reveals slight to moderate dose-dependent downstream effects without functional or clinical symptoms. CONCLUSION: For the time being paclitaxel remains the drug of choice, the dose varies between 2 and 3.5 µg/mm² balloon surface. Neither in animal experiments nor in clinical trials problems have been detected in vessel segments treated with overlapping balloons. Future developments are expected improving efficacy in additional disease conditions (e.g., calcified vessels) and vessel territories.

A novel drug-coated scoring balloon for the treatment of coronary in-stent restenosis: Results from the multi-center randomized controlled PATENT-C first in human trial

ACKGROUND:Scoring balloons produce excellent acute results in the treatment of in-stent restenosis (ISR), fibro-calcific and bifurcation lesions but have not been shown to affect the restenosis rate. A novel paclitaxel-coated scoring balloon (SB) was developed and tested to overcome this limitation.METHODS AND RESULTS:SB were coated with paclitaxel admixed with a specific excipient. Patients at four clinical sites in Germany and one in Brazil with ISR of coronary bare metal stent (BMS) were randomized 1:1 to treatment with either a drug-coated or uncoated SB. Baseline and 6-month follow-up quantitative coronary angiography was performed by an independent blinded core lab and all patients will be evaluated clinically for up to one year. The primary endpoint was angiographic in-segment late lumen loss (LLL). Secondary endpoints included the rate of clinically driven target lesion revascularization (TLR), composite of major adverse cardiovascular events (MACE), stent thrombosis and other variables. Sixty-one patients were randomized (28 uncoated and 33 drug-coated SB); mean age 65 years, males 72%, and presence of diabetes 39%. At 6-month angiography, in-segment LLL was 0.48 ± 0.51 mm in the uncoated SB group versus 0.17 ± 0.40 mm in the drug-coated SB group (P = 0.01; ITT analysis). The rate of binary restenosis was 41% in the uncoated SB group versus 7% in the drug-coated SB group (P = 0.004). The MACE rate was 32% with the uncoated SB vs. 6% in the drug-coated SB group (P = 0.016). This difference was primarily due to the reduced need for clinically driven TLR in the coated SB group (3% vs. 32% P = 0.004)...

Drug-coated balloons for restenosis prophylaxis.

Drug-coated balloons for restenosis prophylaxis provide a high local drug concentration with minimal or no systemic adverse effects. Their development was both delayed and facilitated by the introduction of drug-eluting stents: delayed because sustained release kinetics from stent platforms seemed to be essential and facilitated because prior experience with stents allowed selection of testing methods and drugs. Currently, a variety of drug-coated balloons are available, basically consisting of a coating containing paclitaxel at a dose of about 3 µg/mm² balloon surface, and different additives influencing the adherence and release of the drug, e. g., contrast agent, urea, or various amphiphilic compounds. The drug is almost completely released during a single inflation of 30 - 60 seconds. Studies in animals and several independent randomized clinical trials in coronary and peripheral arteries demonstrate effective reduction of neointimal proliferation, restenosis, and revascularization persisting for at least 2 years or 5 years according to one study in coronary arteries. Drug-coated balloons are preferably used for treating coronary in-stent restenosis and de novo and restenotic lesions in peripheral vessels. No coating-related adverse events have been observed in clinical trials. Persistent efficacy may be explained by the long residence time of paclitaxel in tissue or inhibition of an essential first step in the chain of events leading to neointimal proliferation.

Intracoronary local paclitaxel delivery by X-ray contrast media for in-stent restenosis: a clinical pilot study to assess safety and tolerability.

AIM: Non-stent-based immediate release formulations of paclitaxel have been shown to reduce in-stent restenosis in animal experiments and clinical trials. In the porcine overstretch model paclitaxel dissolved in the contrast medium iopromide inhibited neointimal proliferation in a dose-dependent manner after intracoronary injection and was well tolerated. METHODS: As a first step entering clinical development, a phase I trial was performed using four ascending paclitaxel dose/concentration levels: samples of up to 100 mL of the contrast medium (iopromide) containing 10, 50, 100 or 200 µM paclitaxel or iopromide (controls) were randomly administered to patients assigned to bare metal stent implantation for single de novo coronary artery lesions. Safety variables, tolerability and angiographic parameters were assessed. RESULTS: Adverse events, ECG, systolic and diastolic blood pressure, left ventricular ejection fraction, leukocyte count, other hematological or clinical chemistry data did not reveal any trend which could be related to the study medication. Short-lasting serum paclitaxel concentrations remained significantly below those known from cancer therapy. Angiographic late lumen loss was 0.72±0.50 mm (N.=7) in controls versus 0.45±0.65 mm (N.=17) in all paclitaxel-treated patients; binary restenosis rate was 5/7(63%) versus 6/17 (35%) and target lesion revascularization rate was 4/8 (50%) versus 4/24 (17%). CONCLUSION: Intracoronary infusion of paclitaxel dissolved in an X-ray contrast medium was well tolerated. The results show restenosis inhibition, but the number of patients examined was too small to demonstrate a statistically significant inhibition.

Review of clinical data with Paccocath- coated balloon catheters.

The use of drug-coated balloons (DCB) for preventing restenosis in both coronary and peripheral arteries has received increasing attention. The first successful clinical outcomes in inhibiting restenosis have been reported for paclitaxel-coated balloons. Paclitaxel is a lipophilic substance characterized by rapid intracellular uptake and irreversible binding to microtubules. In this way, paclitaxel alters the cell structure, ultimately reducing proliferation, migration, and signaling. These properties make paclitaxel a very potent antiproliferative drug. Paclitaxel admixed to a small amount of the hydrophilic X-ray contrast medium iopromide (Ultravist™) emerged as a very effective coating matrix from numerous in vitro and in vivo experiments and has been denoted as Paccocath™. The randomized controlled ISR I/II-, Thunder- and FEMPAC studies have been conducted using Paccocath™ balloons. Late lumen loss as the primary endpoint at 6 months proved to be statistically significantly reduced in the coated balloon groups in coronary and peripheral arteries. The slightly modified coating on the SeQuent™ Please balloons (B.Braun, Melsungen, Germany) has been clinically studied in the PEPCAD (Paclitaxel-Eluting PTCA-Catheter in Coronary Artery Disease) clinical trial program. Cotavance™ balloons (MEDRAD Inc, Minneapolis, USA) are also coated with the Paccocath™ formulation. In this review we first outline the development of Paccocath™ balloons to then provide an overview of the clinical results obtained with the modified coating. Furthermore we examine possible mechanism of action by which single administration of an antiproliferative drug dose using paclitaxel-coated balloons inhibits restenosis.

Contemporary issues in cardiac pacing.

This article addresses current pacing practices and issues. Pacing, sensing, sensing amplifiers, and pacing leads are discussed. Cardiac resynchronization is reviewed. Issues of ventricular pacing avoidance, pacemaker lead infections, ionizing radiation effects on pacing and pacing issues after deterioration and expiration of the patient are considered.

Paclitaxel-coated balloons - Survey of preclinical data.

Restenosis following interventions in the coronary or peripheral arteries develops over weeks to months. In coronary arteries the restenosis rate has been markedly reduced since the advent of drug-eluting stents. Non-stent-based methods for local drug delivery enable restenosis inhibition without the need for stent implantation, does not permanently change the structure of the vessel, are repeatable, and seems to be applicable where drug-eluting stents provide insufficient protection. Preclinical data indicate that short exposure of the vessel wall to a lipophilic inhibitor of cell proliferation is sufficient for preventing restenosis. Initial evidence to this effect emerged from an investigation of paclitaxel embedded in a matrix that enhances the solubility and release of the agent from the balloon coating as well as its transfer to the vessel wall. Further corroborating data from preclinical and clinical studies demonstrating a reduction in late lumen loss and lower restenosis rates led to the market introduction of a variety of paclitaxel-coated angioplasty balloons. The effectiveness of restenosis inhibition is not determined by the active agent alone. Other factors that are crucial for the effectiveness and safety of drug-coated angioplasty balloons are the formulation containing the agent and the coating technique. In this review we first outline the development of paclitaxel-coated balloons to then provide an overview of the preclinical results obtained with different paclitaxel-coated balloons and finally compare these with the outcome in patients. The article concludes with a short outlook on initial results with a zotarolimus-coated angioplasty balloon.

Treatment of coronary in-stent restenosis with a novel paclitaxel urea coated balloon.

Randomized clinical trials investigating the treatment of coronary in-stent restenosis with paclitaxel iopromide coated balloon catheters have shown favorable results. The aim of the present clinical investigation was to assess the efficacy of a novel paclitaxel urea coated angioplasty balloon in the treatment of coronary in-stent restenosis. A total of 26 restenotic bare metal stents in 23 patients with a lesion length of 22.8 ± 11.1 mm and a reference vessel diameter of 2.64 ± 0.31 mm were treated. Up to six months and including the six-month angiographic control, only one target lesion revascularization was necessary; in total, the rate of major adverse cardiovascular events until six-month follow-up was 4.3 %. In-stent late lumen loss was 0.07 ± 0.37 mm, in-segment late lumen loss 0.02 ± 0.50 mm. Binary restenosis was present in one patient (4.3%). The results of this first-in-human series with a paclitaxel urea coated balloon are comparable to paclitaxel iopromide coated balloon catheters. Randomized, controlled clinical trials are warranted to further evaluate this promising approach.

Advances on drug-coated balloons.

During the last decades considerable advances have been made in intravascular interventions for the treatment of coronary and peripheral arterial disease. However, long-term outcome remains an area of concern in many applications. Restenosis is still a challenge in endovascular medicine and has thus been referred to as the Achilles' heel of percutaneous intervention. Therefore, novel strategies have been developed to overcome this problem. These include drug-eluting stents, though still associated with stent thrombosis and in-stent restenosis, and the more recently introduced non-stent based local drug delivery systems, especially the paclitaxel-eluting balloon. Results of several preclinical and clinical studies indicate that short-term exposure of injured arteries to paclitaxel eluted from regular PTA and PTCA balloons may be sufficient to reduce late lumen loss and restenosis rates during a critical period of time after angioplasty of diseased coronary and peripheral arteries. Although the number of published trials and patients treated is still limited, available data seem to prove that restenosis inhibition by immediate drug release is feasible. This article reviews the rationale for the use of paclitaxel-coated balloons, data from preclinical and clinical studies, and the perspective of drug-coated balloons in peripheral arterial disease.

Cell-dependent influence on the phagocytosis induced by non-ionic contrast medium injection.

Iodinated contrast media (CM) can inhibit phagocytosis. To better understand the importance of this effect upon the elementary defence mechanism, the aim of the study was to compare the in vivo effect of non-ionic CM on the engulfing ability of peripheral blood phagocytic cells from patients undergoing CM-enhanced CT. Neutrophil granulocytes and monocytes from patients' peripheral blood obtained before and 30 min after CM injection were incubated with fluorescent-labelled Escherichia coli bacteria. Both the percentage of cells that engulfed bacteria and the phagocytic activity per cell has been determined by flow cytometry. We found that phagocytosis was greater in neutrophils than in monocytes. CM decreased the percentage of monocytes phagocyting bacteria, both at 4 degrees C (20.3%+/-3.3% versus 16.1%+/-2.0%; p<0.03) and at 37 degrees C (51.6%+/-4.1% versus 47.5%+/-2.6%; p>0.05), and increased the percentage of neutrophils at 4 degrees C (11.8%+/-2.1% versus 14.3%+/-2.2%; p<0.002) and at 37 degrees C (83.1%+/-3.6% versus 85.1%+/-3.2%; p>0.05). The phagocytic activity decreased significantly at 37 degrees C in monocytes (p<0.02), and was not affected in neutrophils. CM injection has different effects on both the percentage of phagocytosing cells and the phagocytic activity in monocytes and neutrophils. The inhibitory effect on monocyte phagocytosis seems to be compensated by neutrophils.

[Non-ionic iodinated dimeric versus monomeric X-ray contrast media: effects on complement factors in vivo]. / Nichtionische iodierte dimere versus monomere Röntgenkontrastmittel: Effekte auf Komplementfaktoren in vivo.

PURPOSE: To survey contrast media (CM)-induced alterations of complement factors. MATERIAL AND METHODS: In 31 adult patients, who received either an iotrolan (n = 19) or iopromide (n = 12) i. v. injection for CT examination, complement factors C1 q, C3, C4, C5 a, and C1-esterase inhibitor in serum/plasma samples were analyzed. The samples were obtained prior to and 5 min., 30 min., 1 hr., 6 hrs. and 24 hrs. after CM injection. RESULTS: 5 patients (16.1 %) developed a CM reaction. 4 of these were patients who received iotrolan. Other than minimal data, we neither found a significant influence of the CM on complement activation nor a difference between the analyzed CM. In detail, 5 min. after CM administration, we found the tendency to be for the values to decrease and then to return to the basic value. The changes induced by iotrolan were more pronounced than those induced by iopromide; nevertheless the differences were not statistically significant. A more pronounced decrease of C3 and C4 after iotrolan injection indicates the activation of the classic way, while this could not been observed after iopromide injection. One patient who experienced an unwanted reaction towards iotrolan showed shifts of C1 q, C1 INH, C3 and C4. CONCLUSION: The presented data shows different influences of CM injection on the analyzed complement factors after 5 min. that were commonly no longer present 30 min. after CM injection. The dimeric iotrolan induced a significantly increased frequency of unwanted CM reactions than the monomeric iopromide. The question of whether iotrolan is possibly able to activate the classic way of the complement cascade should be analyzed in the future in a greater patient group.

[Current concepts and recent developments of laser ablation in tumor therapy]. / Aktueller Stand und Entwicklungen der Laserablation in der Tumortherapie.

PURPOSE: The purpose of this paper is to present technical innovations and clinical results of percutaneous interventional laser ablation of tumors using new techniques. METHODS; Laser ablation was performed in 182 patients (liver tumors: 131, non hepatic tumors-bone, lung, others: 51) after interdisciplinary consensus was obtained. The procedure was done using a combination of imaging modalities (CT/MRI, CT/US) or only closed high field MRI (1.5 T). All patients received an MRI-scan immediately after laser ablation. RESULTS: In 90.9% of the patients with liver tumors, a complete ablation was achieved. Major events occurred in 5.4%. The technical success rate of laser ablation in non-hepatic tumors was high, clinical results differed depending on the treated organ. CONCLUSIONS: The treatment of tumors of the liver and other organs up to 5 cm by laser ablation was a safe procedure with a low rate of complications and side effects. Image guidance by MRI is advantageous for precise tumor visualization in all dimensions, therapy monitoring, and control of laser ablation results.

Double contrast MRI of thermally ablated liver metastases.

PURPOSE: To investigate the ability of double contrast MRI (enhancement with iron oxide and gadopentetate dimeglumine) to increase the difference in contrast between various tissues after thermal ablation of liver metastases. MATERIALS AND METHODS: 12 patients were imaged after MR-guided laser-induced thermotherapy (LITT). Imaging was performed with a 1.5T MR system. Nonenhanced, iron oxide-enhanced and double contrast images were acquired using T (1)-weighted GRE and T (2)-weighted TSE sequences. Iron oxide imaging was performed 10 min after injection of 1.4 ml ferucarbotran (Resovist(R), Schering AG Berlin, Germany) and double contrast imaging 60 sec after the additional injection of 0.1 mmol/kg body weight gadopentetate dimeglumine (Magnevist(R), Schering AG Berlin, Germany). Qualitative and quantitative assessment was performed on induced necroses, residual or recurrent tumor tissue and metastatic tissue untreated at the time of the study. RESULTS: Iron oxide-enhanced T (1) GRE images demonstrated the highest contrast between ablated hyperintense tissue and iron accumulating and resultant hypointense liver parenchyma. Due to Gd enhancement, double contrast T (1)-weighted GRE images displayed the highest change in signal intensity in vital tumor tissue compared to ablated tissue and iron oxide accumulating liver parenchyma (p < 0.01). CONCLUSIONS: First observations indicate that LITT of hepatic metastases can be better followed with double contrast MRI, which displays increased contrast due to Gd enhancement of perfused tumor tissue and signal intensity loss in iron oxide accumulating hepatic parenchyma. Induced necrosis does not change its signal intensity at all after injection of iron oxide and Gd-containing contrast media.

[Laser-induced thermotherapy (LITT) of lung metastases: description of a miniaturized applicator, optimization, and initial treatment of patients]. / Laser-induzierte Thermotherapie (LITT) von Lungenmetastasen: Beschreibung eines miniaturisierten Applikators, Optimierung und erste Patientenbehandlungen.

PURPOSE: A thin-caliber applicator system was developed for introducing a laser fiber under CT guidance into lung metastases with only minimal complications. MATERIALS AND METHODS: A space-saving 5.5 French Teflon cannula with a titanium trocar and connectors for a laser light guide (2 or 3 cm Dornier Diffusor-Tip H-6111-T2 or H-6111-T3 coupled to a Dornier Medilas Fibertom 5100 laser, wavelength of 1064 nm) and a perfusion line for physiologic saline solution were developed. After puncture the laser Diffusor-Tip remains in the cannula and is cooled during its tissue passage by slowly flowing saline solution. The miniaturized applicator system (Monocath) was calibrated in nonperfused bovine liver for maximum energy supply and necessary flow of the cooling saline solution in reference to a commercially available 9 French laser catheter with an 11.5 French inducer sheath (Power-Applicator). The new applicator system was used for treating lung metastases in 10 patients over a period of 21 months. RESULTS: The size of heat coagulation in bovine liver was 24 +/- 2 ml using the miniaturized system with application of 15 W for 20 min and a saline flow of 0.75 ml/min, in comparison to a size of 29 +/- 7 ml for the commercial applicator (30 W, 20 min, 60 ml/min). All metastases could be safely approached with the miniaturized applicator, except for two metastatic lesions at the lung base in two patients. A minor pneumothorax developed in three patients and intrapulmonary bleeding in two. Contrast-enhanced CT demonstrated necrosis of the treated metastatic areas in 6 patients. Follow-up of three patients after 5, 6, and 8 months showed complete tumor regression with minimal scarring in one patient. CONCLUSION: The miniaturized applicator system enables the introduction of a laser fiber into pulmonary metastases with only minor complications. Complete ablation seems to be achievable in suitable patients with the applied laser energy and a slow cooling fluid flow rate.

[Oral contrast media in CT: improvement by addition of guar?]. / Orale Kontrastmittel in der CT: Verbesserung durch Zugabe von Guar?

PURPOSE: To evaluate the additional effect of guar with iotrolan as an oral contrast medium. METHOD: In a clinical double-blind randomised study a viscous iotrolan (11.2 mg iodine/ml)/guar (4 g/l)-suspension was compared with aqueous solutions of pure iotrolan (11.2 mg iodine/ml) and meglumine ioxithalamate (12 mg iodine/ml). The contrast media were evaluated according to filling, distribution, transit time, artifacts, radiodensity, patient acceptance and side effects. RESULTS: The addition of guar delayed the transit time of the contrast media. Consequently a more homogeneous filling of the bowel with fewer artifacts was observed in comparison to the aqueous contrast media. The results of the pure iotrolan solution were comparable to meglumine ioxithalamate, except for a higher radiodensity in the distal small intestine. The colon showed a better filling with non-viscous contrast media in the given time frame. Pure iotrolan had the best patient acceptance. Two patients considered the iotrolan/guar-solution impossible to drink, the other 18 patients found taste and consistency just about acceptable. CONCLUSION: In spite of the discussed advantages, due to a less subjective acceptance the guar/iotrolan solution is not suitable in routine-diagnosis, unless taste and consistency are greatly improved. Individual use is recommended in selected cases and long-term examinations.

Imaging of exocrine pancreatic function. Investigation of the bioavailability of weak organic acids as potential pancreatic contrast agents for computed tomography.

RATIONALE AND OBJECTIVES: The feasibility of targeting iodinated contrast agents to the exocrine pancreas was investigated. Iodinated weak organic acids including succinic acid-mono-3-amino-2,4,6-triiodo- N-ethylanilide (compound I), the ethanolamine salt of N-ethylsuccinic acid-(2,4,6-triiodo-3-methylamino anilide) (compound II), and the sodium salt of 2,4,6-triiodo-3-N-ethylacetylamino-phenylpropionic acid (compound III) were studied as potential contrast agents for computed tomography (CT) of the pancreas. METHODS: An ex vivo perfusion system was used to compare pancreatic uptake of the three compounds. In vivo CT studies were conducted using domestic pigs to study potential enhancement of the pancreas after intravenous injection of the compound. RESULTS: Ex vivo perfusion studies with isolated rat pancreas demonstrated nearly identical extraction ratios of approximately 0.6 for all three compounds tested. Average iodine concentrations measured in pancreas at the end of the perfusion studies was 0.27 mg/g +/- 0.20 for compound I, 0.18 mg/g +/- 0.06 for compound II, and 0.16 mg/g +/- 0.09 for compound III. Differences in iodine concentrations retained were not statistically significant. Computed tomography studies in domestic pigs demonstrated up to 30% enhancement of the pancreas after intravenous injection of 75 and 150 mg/kg of compound II at 45 minutes. Whereas ex vivo perfusion studies indicated increasing extraction of the three compounds with increasing doses/concentrations in the perfusate, no improved contrast enhancement was observed at the higher dose level compared with the lower dose in CT. CONCLUSION: Both ex vivo perfusion studies and dose-independent enhancement levels achieved seem to indicate a transport maximum in the pancreas for the iodinated weak organic acids studied.

Influence of two guar preparations on glycosylated hemoglobin, total cholesterol and triglycerides in patients with diabetes mellitus.

Guar smoothens postprandial glucose peaks and reduces serum cholesterol. Both properties are advantageous for diabetic patients and can be realized, in part, by adding fiber to the diet. Depending on the blood glucose concentration, a small portion is incorporated into hemoglobin (HbA1), building a largely irreversible complex, making it a long-term indicator of blood glucose status. HbA1 may increase from a normal value of about 5% to as much as 20% of total hemoglobin in diabetics. This study tested the efficacy of two guar preparations in diabetic patients over 3 months by measuring HbA1, cholesterol and triglycerides. Forty diabetic patients with HbA1 > 10% ingested either 3 x 4 g daily of a new guar preparation (GU-052, Steigerwald, Darmstadt, Germany) or 3 x 5 g daily of Glucotard (Boehringer, Mannheim, Germany) for 12 weeks. Before and after 30, 60 and 90 days of treatment, HbA1, cholesterol and triglycerides were determined. After 90 days of treatment, GU-052 caused a reduction in HbA1 from 12.6 +/- 2.6% to 10.5 +/- 1.5% (-15.6 +/- 9.0%) in the GU-052 group and from 12.0 +/- 2.6% to 10.9 +/- 1.82% (-8.6 +/- 7.2%) in the Glucotard group. Cholesterol was reduced from 269 +/- 28 mg/100 ml on day 0 to 227 +/- 18 mg/100 ml on day 90 in the GU-052 group and from 261 +/- 40 to 235 +/- 26 mg/100 ml in the Glucotard group. Both GU-052 and Glucotard had little effect on plasma triglycerides. Fewer unpleasant side effects were reported for the GU-052 preparation than for Glucotard.(ABSTRACT TRUNCATED AT 250 WORDS)

Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system.

Gadolinium diethylenetriaminepentaacetic acid (DTPA) covalently linked to the lipophilic ethoxybenzyl moiety (Gd-EOB-DTPA) was designed for use as a contrast agent in hepatobiliary magnetic resonance imaging. With T1 relaxivity values of 8.7 L/mmol.second in plasma and 16.6 L/mmol.second in rat liver tissue and a median lethal dose of 10 mmol/kg when administered intravenously in mice and rats, Gd-EOB-DTPA has a fairly high margin of safety. In rats and monkeys, biodistribution studies performed 7 days after administration of 0.25 mmol/kg revealed very little retention of gadolinium (less than 1%) in the tissues, indicating complete elimination via renal and biliary excretion. Biliary excretion was inhibited by coadministration of sulfobromophthalein, indicating the involvement of a carrier-mediated transport system based on the enzyme glutathione-S-transferase. In rats, the biliary transport maximum was 5 mumol gadolinium/min.kg. High T1 relaxivity of Gd-EOB-DTPA in rat liver in vivo can be explained by transient interaction with intracellular components and by increased microviscosity inside the hepatocyte.