PET Imaging–Based Evaluation of Hepatobiliary Transport in Humans with (15R)-¹¹C-TIC-Me

Abstract

It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of 11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-11 C-TIC-Me)] in healthy subjects. Methods: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-11 C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. Results: After rapid hydrolysis in blood, the acid form-11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-11 C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-11 C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-11 C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. Conclusion: We demonstrated that PET image analysis with (15R)-11 C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…Recently, to non-invasively perform the real-time measurement of the tissue concentration of drugs, several kinds of positron emission tomography (PET) probes for evaluating OATP function have been created and characterized in rodents and humans. [70][71][72][73] By using the time profile data for tissue concentration as well as the plasma concentration of drugs to optimize the model parameters, we can further increase the reliability of a PBPK model. Another strategy is to create methods for extracting multiple candidate sets of model parameters which can reproduce a limited number of clinical data.…”

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

“…CsA, rifampin, and gemfibrozil were used as the strong (CsA and rifampin) or weak (gemfibrozil) OATP1B1 inhibitors in this study because they showed substrate-dependent OATP1B1 inhibition with 6-to 14-fold difference in the K i values when E 2 G, E 1 S, and BSP were used as in vitro test probes (Izumi et al, 2013), and administration of the inhibitors has caused clinical DDIs with OATP1B1 substrate drugs (Shitara et al, 2013b). In fact, inhibition of hepatic uptake by rifampin was demonstrated in healthy subjects by positron emission tomography using 15R-[ 11 C]TIC as an OATP substrate (Takashima et al, 2012). The K i values of CsA, rifampin, and gemfibrozil for the clinically used substrate drug uptake showed 6.3-, 3.4-, and 26-fold variations depending on the substrates, respectively (Table 2).…”

“…The genetic polymorphisms of SLCO1B1 are associated with interindividual variation in the plasma concentrations of 3-hydroxymethylglutarylCoA reductase inhibitors (statins) (Shitara and Sugiyama, 2006) and adverse event rates during simvastatin therapy (Link et al, 2008). In clinical situations, DDIs involving OATP substrate drugs and cyclosporine A (CsA) or a single dose of rifampin are considered to be attributable to the inhibition of OATP1B1 and its closely-related isoform, OATP1B3 (Shitara et al, 2003;Maeda et al, 2011;Takashima et al, 2012). Based on the accumulated evidence, OATP1B1 has been widely recognized as a clinically important transporter, and the evaluation of OATP1B1-mediated DDI potential of drug candidates is crucial in the drug development.…”

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

“…Emerging data on tissue concentrations obtained by advanced imaging methods [33,99], in conjunction with mechanistic PBPK modeling, is envisaged as a powerful tool to improve predictability and understanding of implications of transportermediated tissue distribution and interactions.…”