A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography
| Autor: | Ken-ichi Kaneko, Hiroyuki Kusuhara, Joji Kawabe, Susumu Shiomi, Masaru Enomoto, Kota Toshimoto, Yilong Cui, Yumiko Katayama, Takashi Yamanaga, Hideki Kawahata, Akira Ishii, Takayoshi Nakaoka, Etsushi Kawamura, Masaaki Tanaka, Yuichi Sugiyama, Yasuyoshi Watanabe, Norifumi Kawada, Takeshi Miyake, Yasuhiro Wada, Satsuki Irie, Kazuya Maeda |
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| Rok vydání: | 2018 |
| Předmět: |
Pharmacology
Organic anion transporter 1 biology medicine.diagnostic_test Chemistry Multidrug resistance-associated protein 2 Pharmaceutical Science Urine 030226 pharmacology & pharmacy Excretion 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Positron emission tomography In vivo 030220 oncology & carcinogenesis biology.protein medicine Rifampicin medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 46:719-728 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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