PT - JOURNAL ARTICLE AU - Ken-ichi Kaneko AU - Masaaki Tanaka AU - Akira Ishii AU - Yumiko Katayama AU - Takayoshi Nakaoka AU - Satsuki Irie AU - Hideki Kawahata AU - Takashi Yamanaga AU - Yasuhiro Wada AU - Takeshi Miyake AU - Kota Toshimoto AU - Kazuya Maeda AU - Yilong Cui AU - Masaru Enomoto AU - Etsushi Kawamura AU - Norifumi Kawada AU - Joji Kawabe AU - Susumu Shiomi AU - Hiroyuki Kusuhara AU - Yuichi Sugiyama AU - Yasuyoshi Watanabe TI - A Clinical Quantitative Evaluation of Hepatobiliary Transport of [<sup>11</sup>C]Dehydropravastatin in Humans Using Positron Emission Tomography AID - 10.1124/dmd.118.080408 DP - 2018 May 01 TA - Drug Metabolism and Disposition PG - 719--728 VI - 46 IP - 5 4099 - http://dmd.aspetjournals.org/content/46/5/719.short 4100 - http://dmd.aspetjournals.org/content/46/5/719.full SO - Drug Metab Dispos2018 May 01; 46 AB - Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.