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J Pharm Sci. 2017 Sep;106(9):2558-2565. doi: 10.1016/j.xphs.2017.05.006. Epub 2017 May 10.

Possible Role of Organic Cation Transporters in the Distribution of [11C]Sulpiride, a Dopamine D2 Receptor Antagonist.

Author information

1
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan; Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan.
2
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
3
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan; Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan.
4
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
5
Department of Pharmacy, The University of Tokyo Hospital Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
6
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: kusuhara@mol.f.u-tokyo.ac.jp.
7
Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.

Abstract

We synthesized [11C]sulpiride as a positron emission tomography probe for investigating the drug distribution in the human body. [11C]Sulpiride was injected to healthy male subjects in either tracer dose of [11C]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 [11C]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 (Km 2.6 μM), hOCT2 (Km 68 μM), hMATE1 (Km 40 μM), and hMATE2-K (Km 60 μM). Moreover, the uptake of sulpiride by human hepatocytes was diminished by tetraethylammonium, and saturable with Km of 18 μM. 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 [11C]sulpiride would be a useful radioligand to investigate the organic cation transporters in humans.

KEYWORDS:

PET; distribution; hepatic transport; imaging methods; organic cation transporters (OCTs); renal clearance

PMID:
28499878
DOI:
10.1016/j.xphs.2017.05.006
[Indexed for MEDLINE]

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