Preclinical Evaluation of [18F]LCATD as a PET Tracer to Study Drug-Drug Interactions Caused by Inhibition of Hepatic Transporters

Andrea Testa, Sergio Dall'Angelo, Marco Mingarelli, Andrea Augello, Lutz Schweiger, Andrew Welch, Charles S Elmore, Dana Dawson, Pradeep Sharma, Matteo Zanda

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The bile acid analogue [18F]LCATD (LithoCholic Acid Triazole Derivative) is transported in vitro by hepatic uptake transporters such as OATP1B1 and NTCP and efflux transporter BSEP. In this in vivo ‘proof of principle’ study we tested if [18F]LCATD may be used to evaluate drug-drug interactions (DDIs) caused by inhibition of liver transporters. Hepatic clearance of [18F]LCATD in rats was significantly modified upon co-administration of rifamycin SV or sodium fusidate, which are known to inhibit clinically relevant uptake transporters (OATP1B1, NTCP) and canalicular hepatic transporters (BSEP) in humans. Treatment with rifamycin SV (total dose 62.5 mg Kg-1) reduced the maximum radioactivity of [18F]LCATD recorded in the liver from 14.2 ± 0.8% to 10.2 ± 0.9% and delayed t_max by 90 seconds relative to control rats. AUCliver 0-5min , AUCbile 0-10min and hepatic uptake clearance CLuptake,in vivo of rifamycin SV treated rats were significantly reduced, whereas AUCliver 0-30min was higher than in control rats. Administration of sodium fusidate (30 mg Kg-1) inhibited the liver uptake of [18F]LCATD, although to a lesser extent, reducing the maximum radioactivity in the liver to 11.5 ± 0.3 %. These preliminary results indicate that [18F]LCATD may be a good candidate for future applications as an investigational tracer to evaluate altered hepatobiliary excretion as a result of drug-induced inhibition of hepatic transporters.
Original languageEnglish
Article number3064751
Number of pages10
JournalContrast Media & Molecular Imaging
Publication statusPublished - 30 Jul 2018

Bibliographical note

Acknowledgements: A.T. gratefully acknowledges SINAPSE ( and AstraZeneca (UK) for co-funding a studentship. P.S. and C.S.E. are employees of AstraZeneca Ltd., UK. This project has also received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 675417.


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