Investigation of Transporter-Mediated Drug-Drug Interactions Using PET/MRI

Abstract

Drug disposition consists of absorption, distribution, metabolism and excretion (ADME). For these processes, drugs and drug metabolites have to cross cellular membranes in different organs and tissues (e.g. intestine, liver, kidney, etc.). In many cases, movement of drugs and drug metabolites across cellular membranes is not just a passive diffusion-mediated process but occurs via saturable transmembrane transporters belonging either to the solute carrier (SLC) or adenosine triphosphate-binding cassette (ABC) families. When two drugs, which are recognized by the same SLC or ABC transporters, are co-administered, one drug may induce transporter inhibition/saturation and thereby change the disposition of the other drug as compared to when the drugs are administered alone. This phenomenon has been termed transporter-mediated drug-drug interaction (DDI), which is of great concern in drug development as this may impact drug safety and efficacy [1]. In many cases, changes in the activity of transmembrane transporters may lead to pronounced changes in drug tissue distribution (e.g. liver, kidneys, brain) without changes in drug plasma pharmacokinetics [2]. To assess such tissue DDIs in vivo, a methodology is needed to measure drug tissue concentration levels. The non-invasive nuclear imaging method positron emission tomography (PET) is a very powerful tool for measuring tissue distribution of drugs radiolabelled with positron-emitting radionuclides, such as carbon-11 (11C, half-life: 20.4 min) or fluorine-18 (18F, half-life: 109.8 min), in animals or humans [3, 4]. Dedicated small-animal PET systems allow to measure rodents (mice, rats) with high sensitivity and good spatial resolution. As PET does not provide anatomical information, it needs to be combined with anatomical imaging to allow for better definition of organs or tissues of interest. In this chapter, we provide a case report of how PET in combination with magnetic resonance imaging (MRI) can be used to assess transporter-mediated DDIs in different organs of the mouse.