Biliary Excretion and Pharmacokinetics of a Gadolinium Chelate Used as a Liver-Specific Contrast Agent for Magnetic Resonance Imaging in the Rat

doi:10.1002/jps.2600820809

Journal of Pharmaceutical Sciences

Volume 82, Issue 8, August 1993, Pages 799-803

https://doi.org/10.1002/jps.2600820809 Get rights and content

Abstract

The introduction of a lipophilic moiety into the gadolinium chelate Gd-DTPA (dimeglumine gadopentetate, Magnevist) yielded Gd-EOB-DTPA (short form), which has potential as a magnetic resonance contrast agent for liver mass screening. The pharmacokinetics of Gd-EOB-DTPA in rats is nonlinear because after correction for the 10-fold difference in dose, the area under the curve of plasma concentration versus time from time zero to infinity after single intravenous application of two different doses were not superimposable, and the amounts excreted renally and extrarenally differed significantly. However, for both dose groups tested, the values of renal clearance (9.96 and 11. 1 mL/min ∙ kg, respectively) were close to the value of glomerular filtration in the rat. Michaelis-Menten kinetics in the extrarenal elimination was therefore considered as the rate-limiting process of Gd-EOB-DTPA, the binding to plasma protein of which is small (10.3 ± 1.4%). Thus, biliary elimination was significantly inhibited by the intravenous coadministration of sulfobromophthalein (a decrease from 39.5 ± 3.17 to 30.7 ± 5.30% of the dose was observed from 0 to 90 min postinoculation under coadministration of the inhibitor), whereas tauroglycocholate revealed no effect, indicating the involvement of the so-called organic anion plasma membrane transport system for the hepatic uptake. The transport of Gd-EOB-DTPA from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S- transferase as demonstrated by in vitro binding studies. A hepatobiliary transport maximum of 9.2 μmol/min ∙ kg was evaluated by infusion studies. No metabolites were detected either in the bile or in the urine, and enterohepatic circulation can be excluded.

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The presence of hydrophobic groups on the Gd3+ chelates can cause hepatocellular uptake and excretion into the bile ducts, gall bladder, and intestines, resulting in the visualization of a hyperintense/bright liver by the MRI. Thus, small molecule liver MRI CAs with hydrophobic groups enhance the signal of the normal liver parenchyma, and have been actively investigated for many years [156,157] with some being currently used in clinical practice [158–160]. The mCAs based on polymer carriers are also inclined to accumulate in the liver, and are therefore promising as liver MRI CAs [117].
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In our assay, different to previously described methods, the intact chelate complex was exclusively measured. The sensitivity of the LC–MS/MS assay is at least 50-fold higher than of well established ICP-AES methods [10–13]. The analytical method enabled the quantitative determination of gadoxetate in cell lysates and human serum.
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The aim of this animal study was to evaluate the feasibility of contrast-enhanced magnetic resonance (MR) angiography with two hepatobiliary contrast agents, Gd-DTPA-DeA and Gd-EOB-DTPA. Coronal images of the rat abdomen were acquired using a three-dimensional spoiled gradient recalled sequence before and after the administration of Gd-DTPA-DeA, Gd-EOB-DTPA, or Gd-DTPA. Four sets of postcontrast images were collected every 90 s. Contrast ratios were calculated for the abdominal aorta on the source images, and the retention index was defined as the ratio of the contrast ratio on the last imaging to that on the first postcontrast imaging. Partial minimum intensity projection (MIP) images covering the abdominal aorta were generated from the first and second postcontrast imagings, and the image quality was visually evaluated. The contrast ratio on the first postcontrast imaging was the highest for Gd-DTPA-DeA, followed by Gd-EOB-DTPA and Gd-DTPA. Retention indices were higher with Gd-DTPA-DeA than with Gd-EOB-DTPA and Gd-DTPA, implying a prolonged contrast effect with Gd-DTPA-DeA. On the MIP image from the first postcontrast imaging, delineation of the abdominal aorta tended to be better with Gd-DTPA-DeA and Gd-EOB-DTPA than with Gd-DTPA, and the difference was evident at low injection doses. Image quality for the second postcontrast imaging was higher with Gd-DTPA-DeA than with the other two agents, suggesting a longer imaging window for Gd-DTPA-DeA. In conclusion, Gd-DTPA-DeA and Gd-EOB-DTPA showed stronger contrast enhancement for the rat abdominal aorta and provided MR angiograms of higher image quality when compared with Gd-DTPA at the same injection dose. These hepatobiliary agents may make it possible to perform contrast-enhanced MR angiography even at a low injection dose.
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Research ArticlesBiliary Excretion and Pharmacokinetics of a Gadolinium Chelate Used as a Liver-Specific Contrast Agent for Magnetic Resonance Imaging in the Rat

Abstract

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Biliary Excretion and Pharmacokinetics of a Gadolinium Chelate Used as a Liver-Specific Contrast Agent for Magnetic Resonance Imaging in the Rat