Biological Distribution of Orally Administered [123I]MIBG for Estimating Gastrointestinal Tract Absorption.

Masato Kobayashi,Yuka Muranaka,Takeo Nakanishi,Naoto Shikano,Ikumi Tamai,Ryuichi Nishii,Kodai Nishi,Asuka Mizutani,Hisakazu Komori,Keiichi Kawai

doi:10.3390/pharmaceutics14010061

Abstract

Gastrointestinal tract absorption of cationic anticancer drugs and medicines was estimated using whole-body imaging following oral [123I]MIBG administration. [123I]MIBG was added to cultures of human embryonic kidney (HEK)293 cells expressing human organic anion transporting polypeptide (OATP)2B1, carnitine/organic cation transporter (OCTN)1 and OCTN2, and organic cation transporter (OCT)1, OCT2, and OCT3 with and without cimetidine (an OCTN and OCT inhibitor) and L-carnitine (an OCTN inhibitor). Biodistribution analyses and single-photon emission computed tomography (SPECT) imaging in normal and dextran sodium sulfate (DSS)-induced experimental colitis mice were conducted using [123I]MIBG with and without cimetidine. [123I]MIBG uptake was significantly higher in HEK293/OCTN1, 2, and OCT1-3 cells than in mock cells. Uptake via OCTN was inhibited by L-carnitine, whereas OCT-mediated uptake was inhibited by cimetidine. Biodistribution analyses and SPECT imaging studies showed significantly lower accumulation of [123I]MIBG in the blood, heart, liver, and bladder in DSS-induced experimental colitis mice and mice with cimetidine loading compared with normal mice, whereas significantly higher accumulation in the stomach and kidney was observed after [123I]MIBG injection. [123I]MIBG imaging after oral administration can be used to estimate gastrointestinal absorption in the small intestine via OCTN and/or OCT by measuring radioactivity in the heart, liver, and bladder.

Highlights

[3 H]methyl-4-phenylpyridinium for organic cation/carnitine transporter (OCTN) and organic cation transporter (OCT). [123 I]MIBG uptake was significantly higher in HEK293/OCTN1, HEK293/OCTN2, HEK293/OCT1, HEK293/OCT2, and HEK293/OCT3 cells than in mock cells
In this study, [123 I]MIBG was administered orally to estimate the gastrointestinal this study, I]MIBGanticancer was administered orally to estimate thesmall gastrointestinal tract tract In absorption of[123 cationic drugs and medicines in the intestine. This absorption of cationic anticancer drugs and medicines in the small intestine. This is imis important because individual patients can exhibit differences in gastrointestinal tract portant because individual patients can exhibit differences in gastrointestinal tract absorpabsorption, which can affect the activity of cationic anticancer drugs and medicines
Imaging method that the enables estimation of anticancer gastrointestinal absorptionAn of imaging cationic method that enables of the gastrointestinal tract absorption of useful cationic anticancer anticancer drugs and estimation medicines in small intestine would be a very clinical tool

Summary

Introduction

[123 I]MIBG is primarily transported into cardiac and neuroblastoma cells via organic cation transporter (OCT), including the norepinephrine transporter [3,4]. Many anticancer drugs (e.g., imatinib) and medicines (e.g., metformin, cimetidine, procainamide) are incorporated into the blood from the small intestinal epithelial cell membrane via solute carrier (SLC) transporters. LC/MS requires liquid samples, such as blood or urine to measure gastrointestinally absorbed anticancer drugs and medicines, such liquid samples are affected by gastrointestinal tract absorption and distribution throughout the body. The purpose of this study was to estimate gastrointestinal tract absorption of cationic anticancer drugs and medicines via whole-body imaging following oral [123 I]MIBG administration. Cationic anticancer drugs and medicines primarily accumulate in the liver for metabolism and/or excretion via the urine and/or feces. It may be possible to estimate gastrointestinal tract absorption by focusing on drug-associated radioactivity in the liver and/or bladder

Objectives

Results

Conclusion