Use of PET Imaging to Evaluate Transporter‐Mediated Drug‐Drug Interactions

Abstract

Several membrane transporters belonging to the adenosine triphosphate-binding cassette (ABC) and solute carrier (SLC) families can transport drugs and drug metabolites and thereby exert an effect on drug absorption, distribution, and excretion, which may potentially lead to transportermediated drug-drug interactions (DDIs). Some transporter-mediated DDIs may lead to changes in organ distribution of drugs (eg, brain, liver, kidneys) without affecting plasma concentrations. Positron emission tomography (PET) is a noninvasive imaging method that allows studying of the distribution of radiolabeled drugs to different organs and tissues and is therefore the method of choice to quantitatively assess transporter-mediated DDIs on a tissue level. There are 2 approaches to how PET can be used in transporter-mediated DDI studies. When the drug of interest is a potential perpetrator of DDIs, it may be administered in unlabeled form to assess its influence on tissue distribution of a generic transporter-specific PET tracer (probe substrate). When the drug of interest is a potential victim of DDIs, it may be radiolabeled with carbon-11 or fluorine-18 and used in combination with a prototypical transporter inhibitor (eg, rifampicin). PET has already been used both in preclinical species and in humans to assess the effects of transporter-mediated DDIs on drug disposition in different organ systems, such as brain, liver, and kidneys, for which examples are given in the present review article. Given the growing importance of membrane transporters with respect to drug safety and efficacy, PET is expected to play an increasingly important role in future drug development.

Imaging techniques to study drug transporter function in vivo

“…In parallel to the acceptance of transporters as the key protein systems allowing the crossing of solutes over biological membranes (Giacomini et al, 2010;Hillgren et al, 2013;Suzuki & Sugiyama, 2000; van Montfoort et al, 2003), the role of drug transporters in imaging is increasingly being appreciated (Kannan et al, 2009;Kilbourn, 2017;Kusuhara, 2013;Langer, 2016;Mann et al, 2016;Marie et al, 2017;Stieger et al, 2012;Testa et al, 2015;Van Beers et al, 2012). Noninvasive imaging methods have therefore been developed to reveal and quantify drug transporter function in clearance and non-clearance organs, as a prerequisite to the local pharmacologic/toxicological effect, metabolism and elimination.…”

Role of Transporters in Drug Development

“…[38][39][40] In this supplement, Langer provides an overview of the use of PET imaging to assess the effect of transportermediated DDIs on drug disposition in various organs such as brain, liver, and kidneys. 41 Further, the author postulates that given the growing importance of membrane transporters with respect to drug safety and efficacy, use of PET in assessment of transportermediated DDIs is expected to play an increasingly important role.…”

“…In addition to the use of PBPK modeling to predict tissue concentrations, the role of noninvasive imaging methods such as positron emission tomography (PET) in assessing tissue uptake and interplay between various transporters has been reported in the literature . In this supplement, Langer provides an overview of the use of PET imaging to assess the effect of transporter‐mediated DDIs on drug disposition in various organs such as brain, liver, and kidneys . Further, the author postulates that given the growing importance of membrane transporters with respect to drug safety and efficacy, use of PET in assessment of transporter‐mediated DDIs is expected to play an increasingly important role.…”

Reaction of 11C‐benzoyl chlorides with metalloid reagents: 11C‐labeling of benzyl alcohols, benzaldehydes, and phenyl ketones from [11C]CO

“…PET is a non‐invasive imaging modality in which physiological and biochemical processes can be studied in vivo following the intravenous administration of a radiolabeled bioactive compound called radiotracer . PET is frequently being used in cardiology, neurology, as well as oncology, and more recently has proven to be a valuable technique in drug discovery …”

“…1,2 PET is frequently being used in cardiology, 3 neurology, 4 as well as oncology, 5 and more recently has proven to be a valuable technique in drug discovery. 6,7 The abundance of carbon in organic molecules makes carbon-11 (t 1/2 = 20.4 minutes) an appealing isotope for PET radiotracer development. Carbon-11 is obtained as either [ 11 C]carbon dioxide ([ 11 C]CO 2 ) or [ 11 C]methane from the cyclotron, from which a number of secondary precursors can be obtained by well-established on-line procedures.…”