Evaluation of skin phototoxicity study using SD rats by transdermal and oral administration

Abstract

-Guinea pigs are the most frequently used animals in phototoxicity studies. However, general toxicity studies most often use Sprague-Dawley (SD) rats. To reduce the number of animals needed for drug development, we examined whether skin phototoxicity studies could be performed using SD rats. A total of 19 drugs that had previously been shown to have phototoxic potential and 3 known phototoxic compounds were administered transdermally to guinea pigs and SD rats. Eleven of the potentially phototoxic drugs and 2 of the known phototoxic compounds were also administered orally to guinea pigs and SD rats. After administration, the animals were irradiated with UV-A (10 J/cm 2 ) and UV-B (0.25 J/cm 2 in guinea pigs and 0.031 J/cm 2 in SD rats) with doses based on standard phototoxicity study guidelines and the results of a minimum erythema dose test, respectively. In the transdermal administration study, all of the known phototoxic compounds and 7 of the drugs induced phototoxic reactions. In the oral administration study, both known phototoxic compounds and 5 drugs induced phototoxic reactions in both species; one compound each was found to be toxic only in SD rats or guinea pigs. The concordance rate of guinea pigs and SD rats was 100% in the transdermal administration study and 85% in the oral administration study. This study demonstrated that phototoxicity studies using SD rats have the same potential to detect phototoxic compounds as studies using guinea pigs.

Evaluation of a general toxicity study incorporating phototoxicity assessments in Sprague-Dawley rats

“…Therefore, the drug should have distributed in the skin sufficiently before anesthesia occurred. Moreover, in a previous report (Yonezawa et al, 2015), we showed that the phototoxicity of multiple drugs can be detected under the same anesthesia conditions. Thus, it was confirmed that pentobarbital anesthesia did not affect the phototoxicity evaluation.…”

“…However, further studies are needed in order to confirm that this toxicity evaluation method can also be used to evaluate drugs with accumulative properties, like meloxicam (Seto et al, 2013;Türck et al, 1997), or that are degraded by metabolic enzymes, like amiodarones (Allen, 1993;Elsherbiny et al, 2008;Yonezawa et al, 2015). These drugs may affect the TK parameters throughout the dosing period, and may cause different phototoxic reactions between the first administration and final administration.…”

“…The dose of UV-A was set at 10 J/cm 2 , as is used in typical skin phototoxicity studies (ICH guideline S10, 2013). The dose of UV-B was set at 0.031 J/cm 2 , based on a previous report (Yonezawa et al, 2015). Skin reactions (erythema/eschar and edema formation) were observed 24, 48, and 72 hr after UV irradiation, according to the Draize method (Table 1) (Draize, 1959).…”

“…One half of the back of each animal was covered with aluminum foil, and the animals were irradiated as for the transdermal administration study. The irradiation start time was set based on a previous report (Yonezawa et al, 2015), to ensure that irradiation occurred at around T max . The time- single-dose (n = 5), repeated-dose (n = 5), and repeated-dose plus toxicokinetics (TK; n = 5).…”

“…In a previous study (Yonezawa et al, 2015), we showed that phototoxicity assessments in Sprague-Dawley (SD) rats can detect phototoxic potential to the same degree as those in guinea pigs, which are typically used as an in vivo model (Morikawa et al, 1974). We used SD rats because the ICH guideline S10 (2013) states that animals should be irradiated at approximately the time of maximum concentration (T max ), and therefore phototoxicity studies require the collection of pharmacokinetic (PK) data.…”