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Evidence for the dissociation of the hepatobiliary MRI contrast agent Mn-DPDP
B Gallez1, G Bacic, H M Swartz
1Department of Radiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Abstract:
These experiments assessed and quantitated the release of free manganese Mn++ from the hepatobiliary contrast agent Mn-DPDP (manganese dipyridoxal diphosphate), using several magnetic resonance techniques (EPR spectroscopy, 31P-NMR spectroscopy, and relaxometry) to differentiate between free Mn++ and Mn++ in complexes in various preparations. The presence of calcium and magnesium in physiological concentrations in aqueous solutions induced the release of Mn++ from the complex, as did incubation of the complex in liver homogenates. After intravenous injection of 15 mumol/kg of Mn-DPDP, both EPR and 31P-NMR spectroscopy demonstrated that Mn-DPDP is partly dissociated (approximately 25%) in the liver. By comparing in vitro and ex vivo data from the liver, we concluded that the dissociation of Mn-DPDP occurs primarily in the liver, whereas a minor portion of the dissociated. Mn found in the liver comes from dissociation of the complex in the blood. Most of the dissociated Mn in liver becomes bound to macromolecules and is responsible for the enhancement of relaxivity observed with this agent.
Insights
Manganese dipyridoxal diphosphate (Mn-DPDP) contrast agent releases free manganese (Mn++) primarily in the liver. This dissociation, enhanced by calcium and magnesium, leads to Mn++ binding with liver macromolecules, increasing relaxivity.
Area of Science:
- Hepatobiliary contrast agents
- Magnetic resonance imaging (MRI) contrast mechanisms
- Inorganic and organometallic chemistry
Background:
- Hepatobiliary contrast agents are crucial for diagnostic imaging of liver function.
- Manganese dipyridoxal diphosphate (Mn-DPDP) is a hepatobiliary contrast agent used in MRI.
- Understanding the in vivo behavior and dissociation of Mn-DPDP is essential for interpreting imaging results.
Purpose of the Study:
- To quantify the release of free manganese (Mn++) from Mn-DPDP.
- To investigate the factors influencing Mn-DPDP dissociation in vitro and in vivo.
- To elucidate the mechanism of relaxivity enhancement by Mn-DPDP in the liver.
Main Methods:
- Electron paramagnetic resonance (EPR) spectroscopy to detect free Mn++.
- 31P-NMR spectroscopy to assess Mn-DPDP complex integrity.
- Relaxometry to measure changes in relaxation times.
- In vitro studies with varying ion concentrations and liver homogenates.
- Ex vivo analysis of liver tissue after Mn-DPDP administration.
Main Results:
- Physiological concentrations of calcium (Ca++) and magnesium (Mg++) induced Mn++ release from Mn-DPDP in aqueous solutions.
- Incubation of Mn-DPDP in liver homogenates also resulted in Mn++ release.
- Intravenous injection of Mn-DPDP led to approximately 25% dissociation in the liver, confirmed by EPR and 31P-NMR spectroscopy.
- In vitro and ex vivo data indicated primary dissociation occurs within the liver, with a minor contribution from blood dissociation.
Conclusions:
- Mn-DPDP dissociation primarily occurs in the liver, not significantly in the blood.
- The released free Mn++ binds to liver macromolecules, contributing to the observed enhancement in relaxivity.
- These findings provide critical insights into the pharmacokinetics and mechanism of action of Mn-DPDP as an MRI contrast agent.