In Vivo Measurement of Hepatic Drug Transporter Inhibition with Radiolabeled Bile Acids

Drug-induced liver injury, and more specifically drug-induced cholestasis, is responsible for a large amount of hospitalizations and attrition of new drug candidates in preclinical drug development. Drug-induced cholestasis can be triggered by drugs that are inhibitors of the hepatic bile acid transporters. Therefore, it is of considerable interest in preclinical drug development to detect whether new candidate drugs can cause interference with the hepatic bile acid transporters. Although several cost-effective and fast in vitro assays are available to that end, these do not mimic the in vivo situation completely. In vivo research to monitor a new candidate drug's cholestatic potential is still relevant, yet is time-consuming and requires invasive sampling of a lot of laboratory animals. In this chapter, a protocol is provided to determine in vivo inhibition of the hepatic bile acid transporters in mice, using the nuclear imaging techniques positron emission tomography and single photon emission computed tomography. The protocol includes detailed information on preparation of the animal, scan acquisition, processing, and (statistical) analysis.