In vivo radioactive metabolite analysis for individualized medicine: a basic study of a new method of CYP activity assay using (123)I-IMP

Kodai Nishi; Asuka Mizutani; Naoto Shikano; Ken-Ichi Fujita; Masato Kobayashi; Masahiro Ono; Ryuichi Nishii; Yasutuna Sasaki; Seigo Kinuya; Keiichi Kawai

doi:10.1016/j.nucmedbio.2014.08.015

In vivo radioactive metabolite analysis for individualized medicine: a basic study of a new method of CYP activity assay using (123)I-IMP

Nucl Med Biol. 2015 Feb;42(2):171-6. doi: 10.1016/j.nucmedbio.2014.08.015. Epub 2014 Sep 6.

Authors

Affiliations

¹ Department of Radioisotope Medicine, Atomic Bomb Disease institute, Nagasaki University, Nagasaki, Japan; School of Health Science, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.
² School of Health Science, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.
³ Department of Radiological Sciences, Ibaraki Prefectural University of Health Science, Ibaraki, Japan.
⁴ Institute of Molecular Oncology, Showa University, Tokyo, Japan.
⁵ School of Health Science, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan; Research Center, Nihon Medi-Physics Co., Ltd., Chiba, Japan.
⁶ University of Miyazaki Hospital, Miyazaki, Japan.
⁷ School of Medical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.
⁸ School of Health Science, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan; Biomedical Imaging Research Center, University of Fukui, Fukui, Japan. Electronic address: kei@mhs.mp.kanazawa-u.ac.jp.

PMID: 25441254
DOI: 10.1016/j.nucmedbio.2014.08.015

Abstract

Introduction: (123)I-N-isopropyl-p-iodoamphetamine ((123)I-IMP) is metabolized and converted to (123)I-p-iodoamphetamine ((123)I-PIA) by CYP2C19 in humans. Since variations in (123)I-PIA levels reflect variations in CYP2C19 activity, CYP2C19 activity can be estimated by quantitative analysis of (123)I-PIA levels. Thus, (123)I-IMP administration can provide diagnostic information not only regarding cerebral blood flow (rCBF) but also regarding metabolic function. The aim of the present study was to detect variations in CYP activity in mice using metabolite analysis.

Methods: Metabolism of (125)I-IMP in pooled homogenates of mouse liver (MLH) was analyzed by high-performance liquid chromatography (HPLC) in the presence or absence of NADPH. The amount of (125)I-PIA generated was calculated as the normalized peak area of the chromatogram. Inhibition of (125)I-IMP metabolism was evaluated using the inhibitor SKF-525A. A biodistribution study of (125)I-IMP was performed to determine the organ distribution of (125)I-IMP/(125)I-IMP metabolites and the effect of SKF-525A. Variations in CYP activity in vivo were detected by administration of (123)I-IMP and/or SKF-525A to mice. The liver and the kidney were then excised, homogenized and analyzed using HPLC.

Results: (125)I-IMP was metabolized by MLH in the presence of NADPH, and the production of (125)I-PIA was inhibited by SKF-525A. SKF-525A did not greatly affect the biodistribution of (125)I-IMP/(125)I-IMP metabolites in vivo. Both (123)I-IMP and (123)I-PIA were detected in organs of control mice. However, (123)I-PIA was not detected in the livers or kidneys of mice treated with SKF-525A.

Conclusions: CYP activity in vivo was inhibited by SKF-525A treatment. Variations in CYP activity could be detected in the blood, liver and kidney as changes in the peak area of (123)I-PIA.

Advances in knowledge and implications for patient care: (123)I-IMP metabolite analysis has the potential to provide beneficial information for prediction of the effect of medicines, in addition to its contribution to more accurate rCBF diagnosis that reflects individual CYP activity.

Keywords: (123)I-IMP; CYP activity; Individualized medicine; Metabolite analysis; Mouse.

MeSH terms

Animals
Cytochrome P-450 CYP2C19 / metabolism*
Enzyme Assays / methods*
Inosine Monophosphate / metabolism*
Inosine Monophosphate / pharmacokinetics
Iodine Radioisotopes / metabolism
Male
Mice
Precision Medicine*
Tissue Distribution

Substances

Iodine Radioisotopes
Inosine Monophosphate
Cytochrome P-450 CYP2C19