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

Abstract

Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11C]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 [11C]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 μM), an organic‐anion‐transporting polypeptide, Na+‐taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11C]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.

Physiologically‐Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug–Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations

“…Generally, human PK profiles and DDIs are discussed based on drug concentration in plasma and/or urine, because blood and urine collection are easy and less invasive procedures. However, PET imaging technology by which tissue accumulation of radiolabeled transporter substrates is detectable could fill the current gap for accurate DDI prediction in tissues and help identification of rate‐determining process in the elimination . Ørntoft et al demonstrated that the use of bile acid tracer [ 11 C]‐cholylsarcosine as an example for an imaging marker provided a proof‐of‐concept for the feasibility of visualizing transporter functions involved in bile formation in humans.…”

Use of imaging to assess the activity of hepatic transporters

“…In one study with the radiolabeled statin drug [ 11 C]rosuvastatin in rats, the presence of rifampicin caused a pronounced increase in the blood AUC as well as a reduction in the liver uptake clearance of [ 11 C] rosuvastatin, which was attributed to an inhibition of OATP uptake transporters in rats [94]. Additionally, in one study in healthy human volunteers, intravenous infusion of cyclosporine A caused an increase in the [ 11 C]rosuvastatin blood AUC and also inhibited the liver uptake clearance in three out of four subjects [37]. These results supported an involvement of OATP transporters in the uptake of [ 11 C]rosuvastatin from the blood into the liver in humans.…”

“…In combination with appropriate radiolabeled probe substrates which are transported by one or several hepatic transporters, PET and SPECT have a great potential to assess the activity of hepatic transporters in vivo in humans under various conditions [33]. Moreover, in combination with radiolabeled drugs or drug candidates, these imaging methods can be potentially used to mechanistically assess transporter-mediated DDIs [35] and to validate in vitro-in vivo extrapolation (IVIVE) methods of hepatic drug clearance [36,37]. Another imaging method, which is of considerable clinical interest, is magnetic resonance imaging (MRI) in combination with contrast agents which enter and leave hepatocytes mediated by hepatic transporters [33].…”

“…[ 11 C]rosuvastatin) [37]. Even though such radiotracers may produce a large change in PET signal when the OATP transporters are knocked out or completely inhibited, they may lack the sensitivity to measure small alterations in transporter activity.…”

“…Basolateral backflux might be mediated by basolateral efflux transporters and make a major contribution to total hepatic clearance of a given radiotracer, as in the case of e.g. [ 11 C]rosuvastatin [37]. In addition, in several cases failure to identify a linear phase in the integration plot (in particular for estimation of biliary efflux clearance), makes it often difficult to objectively derive the clearance values from the plot.…”