Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) as contrast agent for magnetic resonance imaging of the liver: mechanistic studies in animals

Abstract

Mechanistic studies regarding the action of gadobenate dimeglumine (Gd-BOPTA/Dimeg; MultiHance) in animals are presented, and the relevance of the results to protocols for MR imaging of the liver are discussed. Gd-BOPTA/Dimeg maintains all the characteristics of an extracellular contrast agent, but owing to a weak affinity for serum albumin, provides in these applications stronger signal intensities than contrast agents without such affinity at the same dose. This property can be taken advantage of for dynamic liver imaging. A unique property of Gd-BOPTA/Dimeg is that the contrast effective ion, Gd-BOPTA2-, enters hepatocytes selectively and reversibly through the sinusoidal plasma membrane using transport mechanisms other than the organic anion transport polypeptide. In a rate-limiting step, the ion is excreted by the multispecific organic anion transporter into the bile. The increase in liver distribution space of Gd-BOPTA2-, as compared to that of purely extracellular contrast agents, is identified as the principal mechanism of normal parenchymal signal enhancement. Microviscosity effects inside hepatocytes add to the relaxation effectiveness of Gd-BOPTA2-, while its presence in the bile and an affinity for intracellular macromolecules play subordinate roles only. Gd-BOPTA2- persists in hepatocytes beyond the times characteristic of dynamic imaging, providing delayed-phase contrast between normal hepatocytes and tumor cells. As a result, the conspicuity of small focal lesions and thus their detection is improved. Additionally, Gd-BOPTA/Dimeg allows sites of abscesses and systemically damaged tissue to be distinguished from healthy liver. Taken together these mechanistically-supported properties qualify the product as a versatile general MR contrast agent with added merits in liver imaging.