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