期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 106, 期 9, 页码 2558-2565出版社
WILEY
DOI: 10.1016/j.xphs.2017.05.006
关键词
organic cation transporters (OCTs); renal clearance; distribution; imaging methods; PET; hepatic transport
资金
- NEDO MicroDose-PJ - New Energy and Industrial Technology Development Organization (NEDO), Japan
- Japan Society for the Promotion of Science [26293032]
- Grants-in-Aid for Scientific Research [16K10356, 26293032] Funding Source: KAKEN
We synthesized [C-11]sulpiride as a positron emission tomography probe for investigating the drug distribution in the human body. [C-11]Sulpiride was injected to healthy male subjects in either tracer dose of [C-11]sulpiride (approximately 222 MBq) or with therapeutic dose of sulpiride (500 mg, peroral) 3 h before the injection in a crossover fashion. Whole-body positron emission tomography imaging demonstrated that [C-11]sulpiride accumulated exceedingly in the bladder, followed by liver, gall bladder, and kidney, respectively, at 30 min after the injection, whereas scarcely in the brain. Oral dose of sulpiride decreased the hepatic accumulation of the radioactivity by 60%. From in vitro experiments, we found that sulpiride is a substrate of hOCT1 (K-m 2.6 mu M), hOCT2 (K-m 68 mu M), hMATE1 (K-m 40 mu M), and hMATE2-K (K-m 60 mu M). Moreover, the uptake of sulpiride by human hepatocytes was diminished by tetraethylammonium, and saturable with K-m of 18 mu M. Oct1/2 double knockout mice and wild-type mice received Mate1 inhibitors (pyrimethamine/cimetidine) manifested reduced renal clearance of sulpiride, accompanied with its accumulation in the plasma. In conclusion, we found that sulpiride is a substrate of OCT1, OCT2, MATE1, and MATE2-K, and this suggests that [C-11]sulpiride would be a useful radioligand to investigate the organic cation transporters in humans. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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