Involvement of organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins (hMATEs) in renal elimination of meta‐iodobenzylguanidine (mIBG)

Abstract

Radiolabeled meta‐iodobenzylguanidine (mIBG) is utilized as both a diagnostic imaging agent (123I‐mIBG) and targeted radiotherapy (131I‐mIBG) for neuroblastoma. mIBG is cleared predominantly by the kidney through glomerular filtration and active secretion. Whole‐body scintigraphy showed rapid uptake and extensive accumulation in non‐tumor tissues, which can interfere with mIBG tumor imaging quality and lead to peripheral toxicities. Although mIBG is known to be transported into neuroblastoma tumor cells by the norepinephrine transporter (NET), the molecular mechanisms underlying mIBG transport in the kidney and non‐tumor tissues are unclear. We hypothesize that human organic cation transporters 1–3 (hOCT1–3) as well as multidrug and toxin extrusion proteins (hMATE1/2‐K) are involved in mIBG renal secretion and uptake in non‐tumor tissues. To test this hypothesis, the uptake of mIBG was measured in HEK293 cell lines stably transfected with hNET, hOCT1, hOCT2, hOCT3, hMATE1 and hMATE2‐K followed by LC‐MS/MS quantification. The transepithelial transport of mIBG was further evaluated utilizing a MDCK cell line co‐transfected with hOCT2 and hMATE1 to model secretion in renal proximal tubule cells. Uptake studies in the HEK293 system demonstrated that mIBG is a universal substrate for hOCT1, 2, 3, hMATE1 and 2‐K. Kinetic analysis further revealed that hOCT1, hOCT2, and hOCT3 transport mIBG with similar apparent affinities (Km of 17.5 ± 5.4, 17.2 ± 2.8, 15.5 ± 6.6 μM, respectively) which are comparable to hNET (Km of 35.7 ± 8.9 μM). In the hOCT2/hMATE1 MDCK cells, the basal‐to‐apical (B‐to‐A) flux of mIBG is much greater than its A‐to‐B flux and increased by 20‐fold as compared to B‐to‐A flux in vector transfected control cells. The apparent B‐to‐A permeability of mIBG in the hOCT2/hMATE1 cells was 12.6 ± 2.7 cm/sec, which is 18‐fold greater than that in control cells. Interestingly, the intracellular accumulation in the hOCT2/hMATE1 cells was increased only by 1.9‐fold as compared to the control cells, suggesting that apical hMATE1 efficiently effluxes mIBG from renal cells after mIBG uptake via OCT2. Together, our data demonstrated that mIBG is efficiently transported by hOCTs and hMATEs and that the hOCT2/hMATEs pathway is involved in active secretion of mIBG in the kidney. Inhibition of hOCT2 and/or hMATEs by other drugs may alter mIBG renal clearance and/or intrarenal accumulation, leading to clinically significant drug‐drug interactions during 131I‐mIBG therapy.Support or Funding InformationThis work is supported by NIH Grants GM066233 and T32‐GM007750.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.