Inhibition of the Hepatic Uptake of 99mTc-Tetrofosmin Using an Organic Cation Transporter Blocker

Kodai Nishi; Masato Kobayashi; Minori Kikuchi; Asuka Mizutani; Yuka Muranaka; Ikumi Tamai; Keiichi Kawai; Takashi Kudo

doi:10.3390/pharmaceutics13071073

Inhibition of the Hepatic Uptake of ^99mTc-Tetrofosmin Using an Organic Cation Transporter Blocker

Pharmaceutics. 2021 Jul 13;13(7):1073. doi: 10.3390/pharmaceutics13071073.

Authors

Kodai Nishi¹, Masato Kobayashi², Minori Kikuchi³, Asuka Mizutani², Yuka Muranaka², Ikumi Tamai⁴, Keiichi Kawai^{2

5}, Takashi Kudo¹

Affiliations

¹ Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
² Faculty of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-1192, Japan.
³ School of Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
⁴ Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
⁵ Biomedical Imaging Research Center, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji, Fukui 910-1193, Japan.

Abstract

The accumulation of high levels of ^99mTc-tetrofosmin (^99mTc-TF) in the hepatobiliary system can lead to imaging artifacts and interference with diagnosis. The present study investigated the transport mechanisms of ^99mTc-TF and attempted to apply competitive inhibition using a specific inhibitor to reduce ^99mTc-TF hepatic accumulation. In this in vitro study, ^99mTc-TF was incubated in HEK293 cells expressing human organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP2B1, organic anion transporter 2 (OAT2), organic cation transporter 1 (OCT1), OCT2, and Na⁺-taurocholate cotransporting polypeptide with or without each specific inhibitor to evaluate the contribution of each transporter to ^99mTc-TF transportation. In vivo studies, dynamic planar imaging, and single photon emission computed tomography (SPECT) experiments with rats were performed to observe alterations to ^99mTc-TF pharmacokinetics using cimetidine (CMT) as an OCT1 inhibitor. Time-activity curves in the liver and heart were acquired from dynamic data, and the ^99mTc-TF uptake ratio was calculated from SPECT. From the in vitro study, ^99mTc-TF was found to be transported by OCT1 and OCT2. When CMT-preloaded rats and control rats were compared, the hepatic accumulation of the ^99mTc-TF was reduced, and the time to peak heart count shifted to an earlier stage. The hepatic accumulation of ^99mTc-TF was markedly suppressed, and the heart-to-liver ratio increased 1.6-fold. The pharmacokinetics of ^99mTc-TF were greatly changed by OCT1 inhibitor. Even in humans, the administration of OCT1 inhibitor before cardiac SPECT examination may reduce ^99mTc-TF hepatic accumulation and contribute to the suppression of artifacts and the improvement of SPECT image quality.

Keywords: 99mTc-tetrofosmin; OCT1; hepatic uptake; small-animal SPECT/CT; transport mechanism.