Development of a Phototoxicity Testing Strategy for Accurate Photosafety Evaluation of Pharmaceuticals Based on the Assessment of Possible Melanin-Binding Effects

Abstract

Drug-induced phototoxicity occurs when drugs absorb natural sunlight, leading to chemical reactions causing cellular damage. Distribution to light-exposed tissues is critical and is enhanced by binding to melanin. The International Council on Harmonization S10 guidance document on photosafety evaluation of pharmaceuticals states that although nonpigmented skin tends to be more sensitive than pigmented skin, pigmented skin models should be considered for drugs that bind significantly to melanin. In this study, an in vitro melanin-binding assay was evaluated as prescreening tool for animal model selection. Binding of various structurally diverse phototoxic drugs to synthetic melanin was investigated in vitro and the high-affinity binder sparfloxacin (SPX), moderate-affinity binder 8-methoxypsoralen (8-MOP), and low-affinity binder pirfenidone (PIF) were selected for in vivo studies. Pigmented Brown Norway (BN) rats were compared with nonpigmented Wistar Albino rats to evaluate their sensitivity for the assessment of phototoxicity and skin concentrations of the drugs were measured. For SPX, the onset of phototoxic symptoms was faster for BN rats and drug concentrations were significantly higher in skin of BN rats. For 8-MOP, both models showed comparable sensitivity and skin concentrations did not differ. For the low-affinity binder PIF, no phototoxic effects were observed and skin concentrations in both models were similar. A combined in vitro/in vivo approach was developed that can be applied for accurate photosafety evaluation of pharmaceuticals based on the assessment of possible melanin-binding effects. In view of the presented data, the pigmented model could be considered for compounds showing a high-affinity binding capacity in vitro.

Phototoxic Reactions Inducted by Hydrochlorothiazide and Furosemide in Normal Skin Cells—In Vitro Studies on Melanocytes and Fibroblasts

“…The formation of drug-melanin complexes may result in much higher concentrations of the drug in the skin, affecting the effectiveness and safety of the treatment, and increasing probability of phototoxic reactions occurrence. Drugs with confirmed ability to bind to melanins are NSAIDs, tetracyclines, and fluoroquinolones [39][40][41]. The observed changes demonstrated in this study suggest a significant contribution of melanin to the cellular response to HCT, FUR, and UVAR.…”

Drug-Induced Photosensitivity—From Light and Chemistry to Biological Reactions and Clinical Symptoms

“…Melanin pigments, both eumelanin and pheomelanin, bind drugs, which affects their efficacy and toxicity as well as the occurrence of side effects. The results of previously conducted studies show that many phototoxic drugs form complexes with melanin polymers [ 69 ]. The percentage of a drug bonded to melanin and the kinetics of drug-melanin complexes formation as well as binding parameters were determined for many phototoxic drugs, including fluoroquinolone antibiotics, tetracyclines, and nonsteroidal anti-inflammatory drugs [ 70 , 71 , 72 ].…”

Adsorption of Diclofenac and PFBS on a Hair Keratin Dimer

“…Many drugs are known to interact with melanin; 19 however, it was recently shown that diclofenac binds only weakly to these polyanionic polymers. 20 Furthermore, Rodri ́guez et al 21 molecular level interactions of keratins with diclofenac and PFBS as model compounds.…”

“…Colored hair contains small pigments that are variants of the polymer melanin. Many drugs are known to interact with melanin; however, it was recently shown that diclofenac binds only weakly to these polyanionic polymers . Furthermore, Rodríguez et al produced activated carbon from tannery hair waste, which exhibited adsorption capability for diclofenac.…”

“…Many drugs are known to interact with melanin; 19 however, it was recently shown that diclofenac binds only weakly to these polyanionic polymers. 20 Furthermore, Rodríguez et al 21 produced activated carbon from tannery hair waste, which exhibited adsorption capability for diclofenac. These indications motivate the study of the molecular level interactions of keratins with diclofenac and PFBS as model compounds.…”