Chimeric mouse model for MRI contrast agent evaluation

Purpose: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)- BOPTA has similar to 50% hepatic clearance in rodents, but similar to 5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion- transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. Methods: FVB (wild- type) and OATP1B1/1B3 knock- in mice were injected with hepatospecific MRI contrast agents (Gd- EOB- DTPA, Gd- BOPTA) and nonspecific Gd- DTPA. T1- weighted dynamic contrast- enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. Results: Following intravenous injection of Gd- BOPTA in chimeric OATP1B1/1B3 knock- in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild- type mice. Gd- BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wildtype mice. Gd- BOPTA elimination in wild- type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd- EOB- DTPA and Gd- DTPA were similar between wild- type and chimeric cohorts. Conclusion: Hepatic MRI signal enhancement and elimination of Gd- EOB- DTPA, Gd- BOPTA, and Gd- DTPA in chimeric OATP1B1/1B3 knock- in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock- in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild- type models.