Characterization of Meta -Iodobenzylguanidine (mIBG) Transport by Polyspecific Organic Cation Transporters: Implication for mIBG Therapy.

Autor: López Quiñones AJ; Department of Pharmaceutics, University of Washington, Seattle, Washington., Wagner DJ; Department of Pharmaceutics, University of Washington, Seattle, Washington., Wang J; Department of Pharmaceutics, University of Washington, Seattle, Washington jowang@uw.edu.
Jazyk: angličtina
Zdroj: Molecular pharmacology [Mol Pharmacol] 2020 Aug; Vol. 98 (2), pp. 109-119. Date of Electronic Publication: 2020 Jun 02.
DOI: 10.1124/mol.120.119495
Abstrakt: Radiolabeled meta -iodobenzylguanidine (mIBG) is an important radiopharmaceutical used in the diagnosis and treatment of neuroendocrine cancers. mIBG is known to enter tumor cells through the norepinephrine transporter. Whole-body scintigraphy has shown rapid mIBG elimination through the kidney and high accumulation in several normal tissues, but the underlying molecular mechanisms are unclear. Using transporter-expressing cell lines, we show that mIBG is an excellent substrate for human organic cation transporters 1-3 (hOCT1-3) and the multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K), but not for the renal organic anion transporter 1 and 3 (hOAT1/3). Kinetic analysis revealed that hOCT1, hOCT2, hOCT3, hMATE1, and hMATE2-K transport mIBG with similar apparent affinities ( K m of 19.5 ± 6.9, 17.2 ± 2.8, 14.5 ± 7.1, 17.7 ± 10.9, 12.6 ± 5.6 µM, respectively). Transwell studies in hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cells showed that mIBG transport in the basal (B)-to-apical (A) direction is much greater than in the A-to-B direction. Compared with control cells, the B-to-A permeability of mIBG increased by 20-fold in hOCT2/hMATE1 double-transfected cells. Screening of 23 drugs used in the treatment of neuroblastoma identified several drugs with the potential to inhibit hOCT- or hMATE-mediated mIBG uptake. Interestingly, irinotecan selectively inhibited hOCT1, whereas crizotinib potently inhibited hOCT3-mediated mIBG uptake. Our results suggest that mIBG undergoes renal tubular secretion mediated by hOCT2 and hMATE1/2-K, and hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. SIGNIFICANCE STATEMENT: mIBG is eliminated by the kidney and extensively accumulates in several tissues known to express hOCT1 and hOCT3. Our results suggest that hOCT2 and human multidrug and toxin extrusion proteins 1 and 2-K are involved in mIBG renal elimination, whereas hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. These findings may help to predict and prevent adverse drug interaction with therapeutic [ 131 I]mIBG and develop clinical strategies to reduce [ 131 I]mIBG accumulation and toxicity in normal tissues and organs.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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