Positron Emission Tomography Imaging of [11C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A

Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [C-11]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [C-11]RSV, estimated through compartment modeling were 1,205.6 +/- 384.8, 16.2 +/- 11.2, and 5.1 +/- 1.8, respectively (n = 6). CsA (blood concentration: 2.77 +/- 0.24 mu M), an organic-anion-transporting polypeptide, Na+-taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [C-11]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 +/- 69%, 384 +/- 102%, and 81 +/- 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.