Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals (Europe) Ltd., Abingdon-on-Thames, UK.
Clin Pharmacol Ther. 2019 Nov;106(5):1056-1066. doi: 10.1002/cpt.1506. Epub 2019 Jul 22.
Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [ C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [ C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 μM), an organic-anion-transporting polypeptide, Na -taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [ C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.
利用正电子发射断层扫描成像技术，我们在健康志愿者中（n=6 无环孢素 A[CsA]，n=4 有环孢素 A）静脉注射未标记的瑞舒伐他汀（RSV；5mg，口服）后，测定了 RSV[ C]（静脉注射）的肝浓度和肝胆转运。通过房室模型估算，RSV 的肝窦摄取、肝窦流出和胆汁流出清除率（CL；mL/min）分别为 1205.6±384.8、16.2±11.2 和 5.1±1.8（n=6）。CsA（血药浓度：2.77±0.24μM），一种有机阴离子转运蛋白，Na -牛磺胆酸钠共转运蛋白和乳腺癌耐药蛋白抑制剂增加了[ C]RSV 的全身血药暴露（45%；P<0.05），降低了其胆汁流出 CL（52%；P<0.05）和肝摄取（25%；P>0.05），但不影响其在肾脏中的分布。CsA 使粪卟啉 I 和 III 及总胆红素的血浆浓度分别增加 297±69%、384±102%和 81±39%（P<0.05）。这些数据可用于未来验证 RSV 肝浓度和肝胆转运的预测。
