Purpose
Phototoxic responses after administration of photosensitive pharmaceutics have been recognized as undesirable side effects, and predicting potential hazardous side effects is gaining importance as new drugs are introduced to the market. In this work, we characterize the photochemical/photobiological properties of model compounds to develop an effective screening method for the prediction of phototoxic/photosensitive potential.
Methods
Twenty-one known photosensitive/phototoxic compounds and five weak/nonphototoxic compounds were subjected to ultraviolet (UV) spectral analyses and photochemical evaluation including the determination of produced reactive oxygen species (ROS) and photostability study. The photooxidation of linoleic acid was also monitored in the presence of tested compounds, guided on the formation of thiobarbituric acid reactive substances.
Results
Most photosensitive/phototoxic drugs tested, even weak UV absorbers, at a concentration of 200 μM showed significant production of ROS under 18 h light exposure (30,000 lx). On the other hand, ROS generated from weak/nonphototoxic compounds, including strong UV absorber benzocaine, were low or negligible. Although exposure of quinine to light resulted in significant degradation (half-life, t 1/2 = 6.4 h), it was dramatically attenuated by the addition of ROS scavengers, especially sodium azide (t 1/2 = 122.6 h). Furthermore, concomitant exposure of photosensitive/phototoxic compounds (200 μM) and linoleic acid (1 mM) for 18 h led to the marked formation of lipoperoxide.
Conclusion
Results indicated that known photosensitive/phototoxic compounds tested have the ability to generate ROS under light exposure, and this photochemical reaction could be associated with their photoinstability and/or phototoxic responses. Based on these findings, determination of ROS, generated from photoirradiated compounds, may be an effective predictive model in recognizing their photosensitive/phototoxic potential.
Similar content being viewed by others
Abbreviations
- BHA:
-
butylated hydroxyanisole
- BHT:
-
butylated hydroxytoluene
- GSH:
-
gluthatione
- MDA:
-
malondialdehyde
- NBT:
-
nitroblue tetrazolium
- NSAIDs:
-
nonsteroidal anti-inflammatory drugs
- ROS:
-
reactive oxygen species
- SDS:
-
sodium dodecyl sulfate
- SOD:
-
superoxide dismutase
- TBARS:
-
thiobarbituric acid reactive substance
- UV:
-
ultraviolet
References
J. H. Epstein (1983) ArticleTitlePhototoxicity and photoallergy in man. J. Am. Acad. Dermatol. 8 141–147 Occurrence Handle1:STN:280:DyaL3s7js1Cluw%3D%3D Occurrence Handle6338062
N. J. Wainwright P. Collins J. Ferguson (1993) ArticleTitlePhotosensitivity associated with antibacterial agents. Drug Safety 9 437–440 Occurrence Handle1:STN:280:DyaK2c7ns1SntQ%3D%3D Occurrence Handle8129863 Occurrence Handle10.2165/00002018-199309060-00006
J. A. Wiebe D. E. Moore (1977) ArticleTitleOxidation photosensitized by tetracyclines. J. Pharm. Sci. 66 186–189 Occurrence Handle1:CAS:528:DyaE2sXht1Oiurg%3D Occurrence Handle14244
F. Vargas I. Martinez Volkmar J. Sequera H. Mendez J. Rojas G. Fraile M. Velasquez R. Medina (1998) ArticleTitlePhotodegradation and phototoxicity studies of furosemide. Involvement of singlet oxygen in the photoinduced hemolysis and lipid peroxidation. J. Photochem. Photobiol., B 42 219–225 Occurrence Handle10.1016/S1011-1344(98)00074-8 Occurrence Handle1:CAS:528:DyaK1cXitlSqsbg%3D
L. Becker B. Eberlein-Konig B. Przybilla (1996) ArticleTitlePhototoxicity of non-steroidal anti-inflammatory drugs: in vitro studies with visible light. Acta Derm.-Venereol. 76 337–340 Occurrence Handle1:STN:280:DyaK2s%2Fks1Srsg%3D%3D Occurrence Handle8891002
P. Ball G. Tillotson (1995) ArticleTitleTolerability of fluoroquinolone antibiotics. Past, present and future. Drug Safety 13 343–358 Occurrence Handle1:CAS:528:DyaK28XnvFyjsw%3D%3D Occurrence Handle8652079
G. Viola G. Miolo D. Vedaldi F. Dall'Acqua (2000) ArticleTitle In vitro studies of the phototoxic potential of the antidepressant drugs amitriptyline and imipramine. Farmaco 55 211–218 Occurrence Handle1:CAS:528:DC%2BD3cXkslKmtbw%3D Occurrence Handle10919085
N. Canudas C. Contreras (2002) ArticleTitleIsolation and identification of the photodegradation products of the photosensitizing antidepressant drug clomipramine. Phototoxicity studies on erythrocytes. Pharmazie 57 405–408 Occurrence Handle1:CAS:528:DC%2BD38XkvVChsLk%3D Occurrence Handle12116878
M. Murata S. Kawanishi (2000) ArticleTitleOxidative DNA damage by vitamin A and its derivative via superoxide generation. J. Biol. Chem. 275 2003–2008 Occurrence Handle1:CAS:528:DC%2BD3cXotFaisg%3D%3D Occurrence Handle10636903
G. Condorelli L. L. Constanzo G. De Guidi ParticleDe S. Giuffrida S. Sortino (1995) ArticleTitleMolecular mechanism of drug photosensitization. 7. Photocleavage of DNA sensitized by suprofen. Photochem. Photobiol. 62 155–161 Occurrence Handle1:CAS:528:DyaK2MXmvFCnu7s%3D Occurrence Handle7638260
I. Kraljic S. E. Mohsni (1978) ArticleTitleA new method for the detection of singlet oxygen in aqueous solutions. Photochem. Photobiol. 28 577–581 Occurrence Handle1:CAS:528:DyaE1MXhslyjtb8%3D
M. A. Pathak P. C. Joshi (1984) ArticleTitleProduction of active oxygen species (1O2 and O2 −.) by psoralens and ultraviolet radiation (320–400 nm). Biochim. Biophys. Acta 798 115–126 Occurrence Handle1:CAS:528:DyaL2cXitVGrsbs%3D Occurrence Handle6322854
H. Ohkawa N. Ohishi K. Yagi (1979) ArticleTitleAssay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95 351–358 Occurrence Handle10.1016/0003-2697(79)90738-3 Occurrence Handle1:CAS:528:DyaE1MXksFaisbk%3D Occurrence Handle36810
I. E. Kocheva (1989) ArticleTitlePhototoxicity of nonsteroidal inflammatory drugs. Coincidence or specific mechanism? Arch. Dermatol. 125 824–826 Occurrence Handle10.1001/archderm.125.6.824 Occurrence Handle1:STN:280:DyaL1M3nt1WnsA%3D%3D Occurrence Handle2730104
N. J. Bunce Y. Kumar L. Ravanal (1979) ArticleTitlePhototoxicity of chlorpromazine. J. Med. Chem. 22 202–204 Occurrence Handle10.1021/jm00188a016 Occurrence Handle1:CAS:528:DyaE1MXms1GgtA%3D%3D Occurrence Handle423200
B. Przybilla A. Georgii T. Bergner J. Ring (1990) ArticleTitleDemonstration of quinolone phototoxicity in vitro. Dermatologica 181 98–103 Occurrence Handle1:CAS:528:DyaK3MXitl2qtbk%3D Occurrence Handle2173670 Occurrence Handle10.1159/000247894
J. P. Martin SuffixJr. K. Colina N. Logsdon (1987) ArticleTitleRole of oxygen radicals in the phototoxicity of tetracyclines toward Escherichia coli B. J. Bacteriol. 169 2516–2522 Occurrence Handle1:CAS:528:DyaL2sXkt1Slsb8%3D Occurrence Handle3034858
D. E. Moore (2002) ArticleTitleDrug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Safety 25 345–372 Occurrence Handle10.2165/00002018-200225050-00004 Occurrence Handle1:CAS:528:DC%2BD38Xlt1Khtrw%3D Occurrence Handle12020173
M. Jeanmougin J. Civatte (1988) ArticleTitlePrediction of benzoyl peroxide phototoxicity by photoepidermotests after repeated applications. Preventive value of a UVB filter. Arch. Dermatol. Res. 280 IssueIDSuppl S90–S93 Occurrence Handle1:CAS:528:DyaL1cXksFSqtrc%3D Occurrence Handle3408262
B. Ljunggren L. E. Wirestrand (1988) ArticleTitlePhototoxic properties of quinine and quinidine: two quinoline methanol isomers. Photodermatology 5 133–138 Occurrence Handle1:CAS:528:DyaL1cXlsVGns70%3D Occurrence Handle3050907
J. E. Allen (1993) ArticleTitleDrug-induced photosensitivity. Clin. Pharm. 12 580–587 Occurrence Handle1:STN:280:DyaK2c%2FjslynsQ%3D%3D Occurrence Handle8222522
J. Mielcarek (1995) ArticleTitleInclusion complexes of nifedipine and other 1,4-dihydropyridine derivatives with cyclodextrins. IV. The UV study on photochemical stability of the inclusion complexes of nisoldipine, nimodipine, nitrendipine and nicardipine with beta-cyclodextrin in the solution. Acta Pol. Pharm. 52 459–463 Occurrence Handle1:STN:280:DyaK2s7hvFCnsw%3D%3D Occurrence Handle8960264
T. Terui H. Tagami (1989) ArticleTitleEczematous drug eruption from carbamazepine: coexistence of contact and photocontact sensitivity. Contact Dermatitis 20 260–264 Occurrence Handle1:STN:280:DyaL1MzisVKlsA%3D%3D Occurrence Handle2752736
A. Leitner P. Zollner (2002) ArticleTitleVisual documentation of the stability of intravenous solutions of omeprazole (Losec) and pantoprazole (Pantoloc). Wien Med. Wochenschr. 152 568–573 Occurrence Handle10.1046/j.1563-258X.2002.02114.x Occurrence Handle1:STN:280:DC%2BD3s%2FgtFSgtA%3D%3D Occurrence Handle12506681
A. Chilin C. Marzano A. Guiotto F. Baccichetti F. Carlassare F. Bordin (2002) ArticleTitleSynthesis and biological evaluation of a new furo[2,3-h]quinolin-2(1H)-one. J. Med. Chem. 45 1146–1149 Occurrence Handle10.1021/jm010993r Occurrence Handle1:CAS:528:DC%2BD38XosV2htQ%3D%3D Occurrence Handle11855995
J. L. Alderfer S. D. Soni A. V. Arakali J. C. Wallace (1993) ArticleTitleUV irradiation of nucleic acids: characterization of photoproducts of thymidylyl-(3′->5′)-2′-deoxy-5-fluorouridine. Photochem. Photobiol. 57 770–776 Occurrence Handle1:CAS:528:DyaK3sXltlCns7Y%3D Occurrence Handle8337248
J. C. Beani R. Gautron P. Amblard F. Bastrenta L. Harrouch P. Jardon J. L. Reymond (1985) ArticleTitleScreening for drug photosensitization activity by measuring the variations in oxygen consumption of Bacillus subtilis. Photodermatology 2 101–106 Occurrence Handle1:CAS:528:DyaL2MXksFSntLw%3D Occurrence Handle3929236
P. Portes M. J. Pygmalion E. Popovic M. Cottin M. Mariani (2002) ArticleTitleUse of human reconstituted epidermis Episkin for assessment of weak phototoxic potential of chemical compounds. Photodermatol. Photoimmunol. Photomed. 18 96–102 Occurrence Handle1:CAS:528:DC%2BD38Xlt1aqu78%3D Occurrence Handle12147043
J. Jagger (1985) Solar–UV Actions on Living Cells Praeger Scientific New York
A. W. Girotti (1990) ArticleTitlePhotodynamic lipid peroxidation in biological systems. Photochem. Photobiol. 51 497–509 Occurrence Handle1:CAS:528:DyaK3cXkt1SitLY%3D Occurrence Handle2188273
J. V. Castell M. J. Gomez-Lechon C. Grassa L. A. Martinez M. A. Miranda P. Tarrega (1994) ArticleTitlePhotodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem. Photobiol. 59 35–39 Occurrence Handle1:CAS:528:DyaK2cXhvVKhsrc%3D Occurrence Handle8127938
J. H. Epstein B. U. Wintroub (1985) ArticleTitlePhotosensitivity due to drugs. Drugs 30 42–57 Occurrence Handle1:STN:280:DyaL2M3osVKnuw%3D%3D Occurrence Handle3896743
S. Brendler-Schwaab A. Czich B. Epe E. Gocke B. Kaina L. Muller D. Pollet D. Utesch (2004) ArticleTitlePhotochemical genotoxicity: principles and test methods. Report of a GUM task force. Mutat. Res. 566 65–91 Occurrence Handle1:CAS:528:DC%2BD2cXpt1Oi Occurrence Handle14706512
InstitutionalAuthorNameBritish Photodermatology Group Workshop C. Arlett L. Earl J. Ferguson N. Gibbs J. Hawk L. Henderson B. Johnson W. Lovell H. D. Menage S. Navaratnam et al. (1995) ArticleTitlePredictive in vitro methods for identifying photosensitizing drugs: a report. Br. J. Dermatol. 132 271–274 Occurrence Handle1:STN:280:DyaK2M7psVyrsw%3D%3D Occurrence Handle7888366
E. Selvaag (1997) ArticleTitleEvaluation of phototoxic properties of oral antidiabetics and diuretics. Photohemolysis model as a screening method for recognizing potential photosensitizing drugs. Arzneim.-Forsch. 47 1031–1034 Occurrence Handle1:CAS:528:DyaK2sXmt12hu70%3D
H. Spielmann M. Liebsch B. Doring F. Moldenhauer (1994) ArticleTitleFirst results of an EC/COLIPA validation project of in vitro phototoxicity testing methods. Altern. Tierexp. 11 22–31
W. W. Lovell P. A. Jones (2000) ArticleTitleEvaluation of mechanistic in vitro tests for the discrimination of photoallergic and photoirritant potential. Altern. Lab. Anim. 28 707–724 Occurrence Handle1:STN:280:DC%2BD3M7gt1Wmug%3D%3D Occurrence Handle11091767
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Onoue, S., Tsuda, Y. Analytical Studies on the Prediction of Photosensitive/Phototoxic Potential of Pharmaceutical Substances. Pharm Res 23, 156–164 (2006). https://doi.org/10.1007/s11095-005-8497-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-005-8497-9