Combined Use of In Vitro Phototoxic Assessments and Cassette Dosing Pharmacokinetic Study for Phototoxicity Characterization of Fluoroquinolones
Journal Title: The AAPS Journal - Year 2011, Vol 13, Issue 3
Abstract
The present study aimed to develop an effective screening strategy to predict in vivo phototoxicity of multiple compounds by combined use of in vitro phototoxicity assessments and cassette dosing pharmacokinetic (PK) studies. Photochemical properties of six fluoroquinolones (FQs) were evaluated by UV spectral and reactive oxygen species (ROS) assays, and phototoxic potentials of FQs were also assessed using 3T3 neutral red uptake phototoxicity test (3T3 NRU PT) and intercalator-based photogenotoxicity (IBP) assay. Cassette dosing pharmacokinetics on FQs was conducted for calculating PK parameters and dermal distribution. All the FQs exhibited potent UV/VIS absorption and ROS generation under light exposure, suggesting potent photosensitivity of FQs. In vitro phototoxic risks of some FQs were also elucidated by 3T3 NRU PT and IBP assay. Decision matrix for phototoxicity prediction was built upon these in vitro data, taken together with outcomes from cassette dosing PK studies. According to the decision matrix, most FQs were deduced to be phototoxic, although gatifloxacin was found to be less phototoxic. These findings were in agreement with clinical observations. Combined use of in vitro photobiochemical and cassette dosing PK data will be useful for predicting in vivo phototoxic potentials of drug candidates with high productivity and reliability.
Authors and Affiliations
Yoshiki Seto, Ryo Inoue, Masanori Ochi, Graham Gandy, Shizuo Yamada, Satomi Onoue
Keywords
Related Articles
- EP ID EP681332
- DOI 10.1208/s12248-011-9292-7
- Views 56
- Downloads 0
Interspecies considerations in the evaluation of human food safety for veterinary drugs
Residues are composed of the parent drug and metabolites, and therefore interspecies comparisons must involve a consideration of comparative xenobiotic metabolism. The focus of this article will be the residue studies th...
Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA
The online version of this article (doi:10.1208/s12248-015-9721-0) contains supplementary material, which is available to authorized users.
Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team
The L2 Global Harmonization Team on large molecule specific assay operation for protein bioanalysis in support of pharmacokinetics focused on the following topics: setting up a balanced validation design, specificity tes...
Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition
The online version of this article (doi:10.1208/s12248-014-9690-8) contains supplementary material, which is available to authorized users.
Molecular Targets and Mechanisms of Cancer Prevention and Treatment by Withaferin A, A Naturally Occurring Steroidal Lactone
The plants used in Ayurvedic medicine, which has been practiced in India for thousands of years for the treatment of a variety of disorders, are rich in chemicals potentially useful for prevention and treatment of cancer...