S4 Integration of imaging techniques to study distribution of drugs in tissues

Hiroyuki Kusuhara , Department of Molecular Pharmacokinetics, the University of Tokyo, Tokyo, Japan
Drug transporters mediate clearance of drugs from the liver and kidney. When tissue uptake processes are carrier-mediated, intrinsic clearance is a complex of tissue uptake, blood-side efflux and subsequent efflux and/or metabolism. Imaging technologies are highly anticipated to elucidate the pharmacokinetic characteristics of drugs that follow the extended clearance concept. Positron emission tomography (PET) is a powerful noninvasive method for molecular imaging in living systems because of its high sensitivity and exceptional spatial–temporal resolution by labeling the compounds by positron emitting isotopes, such as 11C, 15O, and 18F. PET is considered to assist (1) investigation of drug transporter roles in the organs that are not involved in the clearance of drugs, and (2) elucidation of the clearance pathway and factors causing interindividual variation, such as drug–drug interactions (DDI) and genetic polymorphisms, and (3) provision of quantitative biomarkers for pharmacokinetic pharmacodynamic analysis of drugs in humans. We have developed PET probes for drug transporters such as [11C]15R-TIC (OATP1B1/1B3/MRP2), [11C]telmisartan (OATP1B3), [11C]SC-62807 (BCRP), [11C]dehydropravastatin (OATP1B/MRP2), [11C]metformin (OCTs/MATEs) and [11C]sulpiride (OCTs/MATEs). Some of these PET probes have been applied to clinical studies. After intravenous injection, [11C]15R-TIC and [11C]telmisartan accumulated mainly in the liver followed by excretion into the bile. Simultaneous pharmacokinetic analysis of blood and tissue (liver, gall bladder, and bile duct) concentration–time profiles provide tissue uptake and subsequent biliary efflux clearances in human liver. This helps to validate in vitro systems for in vitro–in vivo extrapolation of tissue uptake and canalicular efflux clearances, and to identify sites of DDI. In DDI studies using rifampicin as the perpetrator, in addition to the reduction in the tissue uptake clearance of [11C]15R-TIC mediated by OATP1B, the inhibition of canalicular efflux transporters was suggested as part of the mechanism underlying the inhibition of hepatic clearance. PET has contributed to drug transporter studies of the blood–brain barrier, where ABC transporters are expressed as an active barrier. Inhibition of P-gp significantly elevated the brain AUC of P-gp substrates in humans and nonhuman primates. Bauer et al. demonstrated that the impact of P-gp inhibition is modulated by genotypes of BCRP (421 CC and CA) for [11C]tariquidar, a common P-gp, and BCRP substrate (CPT, 2016). Clinical PET imaging is required to obtain a better understanding of the in vivo significance of drug transporters in the pharmacokinetics of drugs in humans.