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Combined Use of In Vitro Phototoxic Assessments and Cassette Dosing Pharmacokinetic Study for Phototoxicity Characterization of Fluoroquinolones

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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.

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Abbreviations

3T3 NRU PT 3T3:

Neutral red uptake phototoxicity test

ACN:

Acetonitrile

ANOVA:

Analysis of variance

AUC0→∞ :

Area under concentration versus time curve

AUMC0→∞ :

Area under moment curve

C max :

Maximum concentration

CPFX:

Ciprofloxacin

DMEM:

Dulbecco’s modified Eagle’s medium

dsDNA:

Double-stranded DNA

EBSS:

Earle’s balanced salt solution

EMEA:

European Medicines Agency

FDA:

Food and Drug Administration

FQ:

Fluoroquinolone

GFLX:

Gatifloxacin

IBP:

Intercalator-based photogenotoxicity

k el :

Elimination rate constant

K p :

Value tissue to plasma concentration ratio

LFLX:

Lomefloxacin

LVFX:

Levofloxacin

MRT:

Mean residence time

NBT:

Nitroblue tetrazolium

NaPB:

Sodium phosphate buffer

NFLX:

Norfloxacin

OECD:

Organisation for Economic Co-operation and Development

PBS:

Phosphate-buffered saline

PIF:

Photoirritation factor

PK:

Pharmacokinetic

RNO:

p-Nitrosodimethylaniline

ROS:

Reactive oxygen species

SPFX:

Sparfloxacin

t 1/2 :

Elimination half-life

T max :

Time to reach maximum level

TO:

Thiazole orange

UPLC/ESI-MS:

Ultra-performance liquid chromatography equipped with electorospray ionization mass spectrometry

UV:

Ultraviolet

VIS:

Visible light

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Acknowledgments

This work was supported in part by a Grant-in-Aid from the Food Safety Commission, Japan (no. 0807) and a Health Labour Sciences Research Grant from The Ministry of Health, Labour and Welfare, Japan.

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Authors and Affiliations

  1. Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Yoshiki Seto, Ryo Inoue, Masanori Ochi, Shizuo Yamada & Satomi Onoue

  2. Drug Safety Research and Development, Pfizer Global Research and Development, Ramsgate Rd., Sandwich, CT13 9NJ, UK

    Graham Gandy

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  1. Yoshiki Seto
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  2. Ryo Inoue
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  3. Masanori Ochi
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  4. Graham Gandy
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  5. Shizuo Yamada
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  6. Satomi Onoue
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Correspondence to Satomi Onoue.

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Seto, Y., Inoue, R., Ochi, M. et al. Combined Use of In Vitro Phototoxic Assessments and Cassette Dosing Pharmacokinetic Study for Phototoxicity Characterization of Fluoroquinolones. AAPS J 13, 482–492 (2011). https://doi.org/10.1208/s12248-011-9292-7

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