Imaging OATP2B1-mediated transport in the myocardium and lung

Objectives Organic Anion-transporting polypeptides (OATP) form a family of influx transporters with major impact on drug distribution [1]. In vitro studies have shown the expression of OATP2B1 (SLCO2B1, OATP-B) in the vascular endothelium of the human heart, suggesting that OATP2B1 may control the uptake of its substrates into the myocardium [2]. Glyburide (glibenclamide, GLB), an avid OATP2B1 substrate, was isotopically radiolabeled for PET imaging (¹¹C-GLB). Therefore, we used ¹¹C-GLB PET for the functional imaging of OATP2B1-mediated transport in the heart and lung tissue of nonhuman primate.

Methods ¹¹C-GLB PET-CT imaging (222-444 MBq ; 60 min) with measure of arterial input function was performed in two different baboons. In each baboon, we tested the influence of the validated OATP2B1 inhibitor rifampicin (RFA, 8.6 mg/kg i.v) [1] compared to control on ¹¹C-GLB kinetics and distribution (VT ; Logan plot analysis) in two regions of interest drawn on the left ventricular wall and left lung.

Results ¹¹C-GLB area-under-the-curve in arterial plasma was increased 5-fold by RFA. Logan plot analysis, considering arterial input function revealed a significant cardiac uptake (mean VT = 0.40 [0.37-0.44]). RFA administration resulted in a 42% decrease in VT [0.27-0.20] in the heart. Conversely, ¹¹C-GLB distribution in the lung [0.17-0.15] was not as much influenced by RFA treatment [0.16-0.10].

Conclusions The present study provides the first in vivo evidence of the OATP2B1-mediated uptake in the myocardium. Therefore, the cardiac effects of OATP2B1 substrates (e.g GLB, statins, sartans, amiodarone, steroid sulfate conjugates) may be modulated by OATP2B1 function and/or co-administered OATP2B1 inhibitors. Moreover, our results are not in favor with the involvement of OATP2B1 substrate accumulation in the lungs that was proposed as an explanation of amiodarone-induced pulmonary toxicity [3].

Research Support Postes d'accueil CEA/AP-HP