期刊
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
卷 63, 期 2, 页码 205-208出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vascn.2010.10.003
关键词
Ocular drug distribution; Imaging mass spectrometry (IMS); Matrix-assisted laser desorption ionization (MALDI); Ion trap mass spectrometer (MS); Whole-body autoradiography (QWBA)
Introduction: Assessment of drug candidate properties and potential liabilities can greatly benefit from issue driven studies that are designed to address specific toxicological effects such as ocular phototoxicity. If a compound absorbs light in the wavelength range of 290-700 nm (UV-A, UV-B, and visible light) and generates a positive response in a standard in vitro neutral red uptake phototoxicity assay in Balb/c 313 mouse fibroblasts, a single-dose in vivo study may be conducted to assess the potential for drug-induced phototoxicity in the eyes and skin of pigmented Long-Evans rats. Critical to ocular phototoxicity assessment is the hypothesis that the drug or drug-related material must be present in the affected substructures such as the uveal tract, retina, lens, or cornea. For compounds that induce a positive ocular response in the in vivo phototoxicity assay, data on distribution patterns to substructures of the eye can inform decisions regarding the nature of the ocular findings and possibly influence compound advancement. Methods: Quantitative whole-body autoradiography (QWBA) and imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) on an ion trap mass spectrometer employing higher order mass spectrometric scanning functions were utilized for localization of dosed drug or metabolites in eye substructures. Results: In investigative studies designed to simulate an in vivo phototoxicity study, rats were administered radiolabeled test article for QWBA analysis and un-labeled test article for IMS analysis. Autoradiograms from the QWBA study indicated that the radio-labeled analyte(s) preferentially distributed to the uveal tract and not the cornea. However, QWBA did not provide information on the nature of the detected analyte(s); i.e. intact parent drug versus potential metabolites or degradants. Multistage MS experiments performed directly on tissue sections demonstrated semi-quantitative localization in the uveal tract and unequivocal identification of the analyte as the dosed parent drug; no potential metabolites were detected. Discussion: Image analysis by QWBA and IMS by MALDI proved complementary in the localization and identification of small molecule drug distribution within the eye. (C) 2010 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据