Department of Clinical Pharmacology, Medical University of Vienna, A-1090, Vienna, Austria.
Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
Pharm Res. 2021 Jan;38(1):127-140. doi: 10.1007/s11095-021-03002-2. Epub 2021 Feb 8.
To investigate the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of the radiolabeled antiemetic drug [C]metoclopramide in mice with PET.
PET was performed in wild-type mice after administration of an intravenous microdose (<1 μg) of [C]metoclopramide without and with co-administration of either unlabeled metoclopramide (5 or 10 mg/kg) or the prototypical cation transporter inhibitors cimetidine (150 mg/kg) or sulpiride (25 mg/kg). [C]Metoclopramide PET was also performed in wild-type and Slc22a1/2 mice. Radiolabeled metabolites were measured at 15 min after radiotracer injection and PET data were corrected for radiolabeled metabolites.
[C]Metoclopramide was highly metabolized and [C]metoclopramide-derived radioactivity was excreted into the urine. The different investigated treatments decreased (2.5-fold) the uptake of [C]metoclopramide from plasma into the kidney and liver, inhibited metabolism and decreased (up to 3.8-fold) urinary excretion, which resulted in increased plasma concentrations of [C]metoclopramide. Kidney and liver uptake were moderately (1.3-fold) reduced in Slc22a1/2 mice.
Our results suggest a contribution of OCT1/2 to the kidney and liver uptake and of MATEs to the urinary excretion of [C]metoclopramide in mice. Cation transporters may contribute, next to variability in the activity of metabolizing enzymes, to variability in metoclopramide pharmacokinetics and side effects.
利用 PET 研究阳离子转运体（OCT、MATE）在放射性标记止吐药[C]metoclopramide 在小鼠体内的肾和肝处置中的作用。
在未给予和给予未标记 metoclopramide（5 或 10mg/kg）或原型阳离子转运体抑制剂西咪替丁（150mg/kg）或舒必利（25mg/kg）的情况下，给野生型小鼠静脉内给予微量 (<1μg) [C]metoclopramide 后进行 PET。还在野生型和 Slc22a1/2 小鼠中进行了 [C]metoclopramide PET。在放射性示踪剂注射后 15 分钟测量放射性标记代谢物，并对 PET 数据进行放射性标记代谢物校正。
[C]metoclopramide 高度代谢，[C]metoclopramide 衍生放射性活性排入尿液。不同的研究处理减少 (~2.5 倍) [C]metoclopramide 从血浆向肾脏和肝脏的摄取，抑制代谢并减少（高达 3.8 倍）尿液排泄，导致 [C]metoclopramide 血浆浓度增加。Slc22a1/2 小鼠的肾脏和肝脏摄取减少约 1.3 倍。
我们的结果表明 OCT1/2 对肾脏和肝脏摄取和 MATE 对 [C]metoclopramide 的尿液排泄有贡献。阳离子转运体可能与代谢酶活性的变异性一起，对 metoclopramide 药代动力学和副作用的变异性有贡献。
