Key result
MC225 induces cardiovascular effects only at doses ~100 times higher than required for PET imaging.
Why the study?
The potential toxic hazard of the P-glycoprotein substrate MC225 toward the cardiovascular system was not previously evaluated.
Does the novel PET imaging probe MC225 exhibit cardiovascular toxicity at concentrations relevant for in vivo imaging?
Does the novel PET imaging probe MC225 exhibit cardiovascular toxicity at concentrations relevant for in vivo imaging?
MC225 demonstrates a wide cardiovascular safety margin, supporting its development as a PET radiotracer for P-glycoprotein imaging.
Supports MC225 development for P-gp PET imaging; leaves open human cardiovascular safety confirmation.
The P-glycoprotein (P-gp) substrate MC225, at concentrations ≤10 nM, is a valuable radiotracer for positron emission tomography imaging of P-gp function in rats and mice. The aim of this study was to evaluate its potential toxic hazard toward the cardiovascular system through an in-depth analysis of its effects on rat aorta rings, on CaV1.2 channel current (ICa1.2) of A7r5 cells and on Langendorff-perfused rat heart. In aortic rings, MC225 relaxed phenylephrine-induced contraction in a concentration-dependent and endothelium-independent manner, with an IC50 value of about 1 μM. At concentrations ≥3 μM, it antagonized the response to cumulative concentrations of K. MC225, 1 and 10 μM, inhibited ICa1.2 by 15% and 31%, respectively, without affecting either current activation or inactivation kinetics. In Langendorff-perfused rat hearts, only 10 μM MC225 significantly decreased left ventricular pressure and increased coronary perfusion pressure while reducing heart rate and prolonging the cardiac cycle length as well as the atrioventricular conduction time (PQ interval) on the electrocardiogram. Lower concentrations of the drug were ineffective. These findings demonstrate that MC225-induced cardiovascular effects took place at concentrations that are at least 2 orders of magnitude higher than those allowing in vivo measurement of P-gp function. Therefore, MC225 represents a promising positron emission tomography tool for in vivo straightforward P-gp quantification.
No takes yet. Share an insight, caveat, or question.
Fusi et al. (2017) studied Cardiovascular safety evaluation. MC225 was evaluated on Cardiovascular effects (aortic ring relaxation, ICa1.2 inhibition, left ventricular pressure, heart rate). MC225 induced cardiovascular effects only at concentrations ≥1 μM, which is at least 2 orders of magnitude higher than those required for in vivo P-glycoprotein PET imaging.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: