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Organic Cation Transporter 3 Mediates Tissue Uptake and Accumulation of meta-iodobenzylguanidine (mIBG)
Author(s) -
Lopez Quis Antonio,
SalvadorVieira Leticia,
Wang Joanne
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02218
Subject(s) - organic cation transport proteins , norepinephrine transporter , in vivo , crizotinib , chemistry , transporter , in vitro , pharmacokinetics , cancer research , reuptake , pharmacology , medicine , receptor , biochemistry , biology , lung cancer , gene , serotonin , malignant pleural effusion , microbiology and biotechnology
Radioiodinated meta ‐iodobenzylguanidine ( 131 I‐mIBG) is utilized as a targeted radiotherapy for neuroendocrine cancers. 131 I‐mIBG selectively accumulates in the cancer cells through uptake by the norepinephrine transporter. However, whole‐body scintigraphy also shows extensive mIBG uptake and accumulation in several normal tissues (e.g. salivary glands, liver, heart) via mechanisms that are not fully understood. The accumulation of radioactive 131 I‐mIBG in these tissues is associated with a range of adverse reactions and tissue damages due to the unnecessary radiation exposure. We hypothesize that the efficacy and safety of 131 I‐mIBG can be improved by selectively inhibiting mIBG uptake in healthy tissues without affecting its uptake in tumor cells. The goal of this study is to elucidate the impact of organic cation transporter 3 (OCT3) on the in vivo pharmacokinetics andtissue distribution of mIBG using a mouse model with genetic deletion of Oct3 . Additionally, we conducted in vitro studies in HEK293 cell lines stably transfected with mouse Oct3 ( mOct3 ) and human OCT1‐3 (hOCT1‐3) to determine the uptake kinetics of mIBG and dose‐dependent inhibition of OCT1‐3‐mediated uptake of mIBG. The in vitro kinetic analysis revealed similar apparent affinities in the uptake of mIBG by hOCT3 and mOct3 ( K m of 14.5 ± 7.1 and 29.4 ± 3.4 µM, respectively), suggesting minimal species difference in mIBG transport by OCT3. Interestingly, hOCT3‐mediated uptake of mIBG was inhibited by crizotinib ( IC 50 of 2.1 ± 0.3 µM) and crizotinib was 6.7‐fold and 18‐fold more potent towards hOCT3 than for hOCT2 and hOCT1, respectively. For the in vivo pharmacokinetic studies, full concentration‐time profiles were determined to calculate mIBG exposure, defined as area under the concentration‐time curve (AUC), in the plasma and each analyzed tissue. After retro‐orbital injection (10 mg/kg), mIBG exhibited extensive accumulation in all tested tissues with exposures ranging from 4 to 90‐fold higher than the plasma AUC in Oct3 +/+ mice. In contrast, deletion of Oct3 significantly reduced mIBG exposure in the salivary glands by approximately 40%. The exposure of mIBG in the skeletal muscle, heart, and the lungs were also significantly reduced in Oct3 ‐/‐ mice, demonstrating an important role of Oct3 in mediating uptake and accumulation of mIBG in various healthy tissues. On the other hand, the plasma concentration‐time profiles of mIBG were similar between the Oct3 +/+ and Oct3 ‐/‐ mice with no significant changes in systemic AUC and other pharmacokinetic parameters. Additionally, no changes were observed between the two groups in the kidney, the main route of elimination for mIBG, suggesting that Oct3 does not contribute to the renal elimination of mIBG. In summary, we demonstrated that OCT3‐mediated uptake of mIBG can be selectively inhibited and that blocking this pathway leads to decreased mIBG uptake and accumulation in normal tissues. Furthermore, these findings support inhibition of OCT3 as a viable clinical strategy to reduce 131 I‐mIBG accumulation and toxicity in healthy tissues in cancer patients undergoing radiotherapy.