A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C] Dehydropravastatin in Humans Using Positron Emission Tomography
A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C] Dehydropravastatin in Humans Using Positron Emission Tomography
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DOI：
10.1124/dmd.118.080408
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发表时间：
2018-05-01
影响因子：
3.9
通讯作者：
Watanabe, Yasuyoshi
中科院分区：
文献类型：
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作者：
Kaneko, Ken-Ichi;Tanaka, Masaaki;Watanabe, Yasuyoshi
已开发出各种正电子发射断层扫描 (PET) 探针来评估药物转运蛋白在人体内的活性，这有助于预测药物的药代动力学特性以及药物相互作用的影响。我们开发了一种新型PET探针，(3R, 5R)-3, 5-二羟基-7-((1S, 2S, 6S, 8S)-6-羟基-2-甲基-8- ((1-[C-11]-(E)-2-甲基-丁-2-烯酰基)氧基)-1, 2, 6, 7, 8, 8a-六氢萘-1-基)庚酸钠([C-11]DPV)，并证明了其对于大鼠 Oatps（基因符号 SLCO）和 Mrp2（基因符号 ABCC2）定量研究的有用性。为了进一步分析物种差异并验证人体药代动力学参数，以交叉方式对六名健康志愿者进行了腹部区域的连续 PET 扫描，其中使用和不使用 OATP1B 和 MRP2 抑制剂利福平（600 mg，口服），[C-11]DPV。静脉注射后，[C-11]DPV迅速分布到肝脏和肾脏，随后分泌到胆汁和尿液中。利福平显着减少 [C-11]DPV 的肝脏分布 3 倍，导致排泄到胆汁中的量减少 7.5 倍，并延迟 [C-11]DPV 从血液循环中的消除。 [C-11]DPV 的肝脏摄取清除率（CLuptake，肝脏）和小管流出清除率（CLint，胆汁）（分别为每克肝脏 544 +/- 204 和 10.2 +/- 3.5 μl/min）低于先前报道的大鼠中的相应参数（分别为每克肝脏 1800 和 298 μl/min）（Shingaki 等人， 2013）。此外，利福平治疗显着降低了肝脏的 CLuptake 和胆汁的 CLint，分别降低了 58% 和 44%。这些结果表明，[C-11]DPV PET 成像是定量表征人类肝胆转运系统中 OATP1B 和 MRP2 功能的有效工具。
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-[C-11]-(E)-2-methyl-but-2-enoyl)oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl)heptanoate ([C-11]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 [C-11]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, [C-11]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [C-11]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [C-11]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [C-11]DPV(544 +/- 204 and 10.2 +/- 3.5 mu l/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 mu l/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 [C-11]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.