Kosterlitz Centre for Therapeutics and John Mallard Scottish P.E.T. Centre, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca R&D, Pepparedsleden 1, 431 50 Mölndal, Sweden.
Contrast Media Mol Imaging. 2018 Jul 30;2018:3064751. doi: 10.1155/2018/3064751. eCollection 2018.
The bile acid analogue (LithoCholic Acid Triazole Derivative) is transported in vitro by hepatic uptake transporters such as OATP1B1 and NTCP and efflux transporter BSEP. In this in vivo "proof of principle" study, we tested if may be used to evaluate drug-drug interactions (DDIs) caused by inhibition of liver transporters. Hepatic clearance of in rats was significantly modified upon coadministration of rifamycin SV or sodium fusidate, which are known to inhibit clinically relevant uptake transporters (OATP1B1, NTCP) and canalicular hepatic transporters (BSEP) in humans. Treatment with rifamycin SV (total dose 62.5 mg·Kg) reduced the maximum radioactivity of recorded in the liver from 14.2 ± 0.8% to 10.2 ± 0.9% and delayed by 90 seconds relative to control rats. AUC, AUC and hepatic uptake clearance CL of rifamycin SV treated rats were significantly reduced, whereas AUC was higher than in control rats. Administration of sodium fusidate (30 mg·Kg) inhibited the liver uptake of , although to a lesser extent, reducing the maximum radioactivity in the liver to 11.5 ± 0.3%. These preliminary results indicate that may be a good candidate for future applications as an investigational tracer to evaluate altered hepatobiliary excretion as a result of drug-induced inhibition of hepatic transporters.
胆酸类似物（LithoCholic Acid Triazole Derivative）在体外通过肝摄取转运体（如 OATP1B1 和 NTCP）和外排转运体 BSEP 进行转运。在这项体内“原理验证”研究中，我们测试了是否可以使用来评估抑制肝转运体引起的药物相互作用（DDI）。当与利福霉素 SV 或钠夫西地酸共同给药时，大鼠中 的肝清除率明显改变，这两种药物已知在人类中抑制临床相关的摄取转运体（OATP1B1、NTCP）和胆小管肝转运体（BSEP）。利福霉素 SV（总剂量 62.5mg·kg）治疗将肝中记录的 的最大放射性从 14.2±0.8%降低至 10.2±0.9%，并相对于对照大鼠延迟 90 秒。利福霉素 SV 处理大鼠的 AUC、AUC 和肝摄取清除率 CL 显著降低，而 AUC 高于对照大鼠。钠夫西地酸（30mg·kg）给药抑制了 的肝摄取，尽管程度较小，将肝中的最大放射性降低至 11.5±0.3%。这些初步结果表明，可能是未来作为研究示踪剂应用的良好候选物，用于评估药物诱导的肝转运体抑制导致的改变肝胆排泄。
