| Prediction of phospholipidosis-inducing potential of drugs by in vitro biochemical and physicochemical assays followed by multivariate analysis. | |
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MedLine Citation:
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PMID: 19786086 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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An in vitro method to predict phospholipidosis-inducing potential of cationic amphiphilic drugs (CADs) was developed using biochemical and physicochemical assays. The following parameters were applied to principal component analysis, as well as physicochemical parameters: pK(a) and clogP; dissociation constant of CADs from phospholipid, inhibition of enzymatic phospholipid degradation, and metabolic stability of CADs. In the score plot, phospholipidosis-inducing drugs (amiodarone, propranolol, imipramine, chloroquine) were plotted locally forming the subspace for positive CADs; while non-inducing drugs (chlorpromazine, chloramphenicol, disopyramide, lidocaine) were placed scattering out of the subspace, allowing a clear discrimination between both classes of CADs. CADs that often produce false results by conventional physicochemical or cell-based assay methods were accurately determined by our method. Basic and lipophilic disopyramide could be accurately predicted as a nonphospholipidogenic drug. Moreover, chlorpromazine, which is often falsely predicted as a phospholipidosis-inducing drug by in vitro methods, could be accurately determined. Because this method uses the pharmacokinetic parameters pK(a), clogP, and metabolic stability, which are usually obtained in the early stages of drug development, the method newly requires only the two parameters, binding to phospholipid, and inhibition of lipid degradation enzyme. Therefore, this method provides a cost-effective approach to predict phospholipidosis-inducing potential of a drug. |
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Authors:
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Yukihiro Kuroda; Madoka Saito |
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Publication Detail:
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Type: Journal Article Date: 2009-09-26 |
Journal Detail:
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Title: Toxicology in vitro : an international journal published in association with BIBRA Volume: 24 ISSN: 1879-3177 ISO Abbreviation: Toxicol In Vitro Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-22 Completed Date: 2010-06-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8712158 Medline TA: Toxicol In Vitro Country: England |
Other Details:
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Languages: eng Pagination: 661-8 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2009 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Physical Chemistry, School of Pharmaceutical Sciences, Mukogawa Women's University, 46-29, Koshien-kyubancho, Nishinomiya 663-8179, Japan. kurodada@mukogawa-u.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cations Diphenylhexatriene Fluorescent Dyes Humans Lipidoses / chemically induced* Microsomes / enzymology Multivariate Analysis* Pharmaceutical Preparations / adverse effects* Phospholipases A2 / antagonists & inhibitors Principal Component Analysis* Protein Binding |
| Chemical | |
Reg. No./Substance:
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0/Cations; 0/Fluorescent Dyes; 0/Pharmaceutical Preparations; 1720-32-7/Diphenylhexatriene; EC 3.1.1.4/Phospholipases A2 |
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