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

• Main Authors: Kodai Nishi, Masato Kobayashi, Minori Kikuchi, Asuka Mizutani, Yuka Muranaka, Ikumi Tamai, Keiichi Kawai, Takashi Kudo
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Pharmaceutics
• Subjects: ^99mTc-tetrofosmin; small-animal SPECT/CT; hepatic uptake; transport mechanism; OCT1
• Online Access: https://www.mdpi.com/1999-4923/13/7/1073

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.