Photosafety Screening of Phenothiazine Derivatives With Combined Use of Photochemical and Cassette-Dosing Pharmacokinetic Data

Abstract

This study aimed to establish an efficient photosafety screening system, employing in vitro photochemical and cassette-dosing pharmacokinetic (PK) studies. Eight phenothiazine (PTZ) derivatives were selected as model chemicals, and photochemical characterization and cassette-dosing PK study were carried out. In vivo photosafety testing on oral PTZs (100 mg/kg) was also assessed in rats. All the tested PTZs exhibited potent UVA/B absorption with molar extinction coefficients of ca. 3400-4400 M(-1)cm(-1). Under exposure to simulated sunlight (2.0 mW/cm(2)), all PTZs, especially fluphenazine 2HCl (FP) and trifluoperazine 2HCl (TF), tended to generate reactive oxygen species (ROS). Casset-dosing PK studies demonstrated high dermal deposition of FP and TF in rats, and from these findings, taken together with the potent photochemical reactivity, both FP and TF were deduced to be highly phototoxic. In contrast, the phototoxic potential of chlorpromazine HCl (CP) seemed to be low because of moderate ROS generation and limited dermal distribution. Predicted phototoxic risk for PTZs from photochemical and PK data appeared basically to agree with the observed phototoxicity in rats; however, oral CP (100 mg/kg) caused severe phototoxic responses in rats. Metabolites of CP have been recognized to be phototoxic, which might explain in part this false prediction. These findings might also suggest the necessity of complementary testing on drug metabolites for more reliable photosafety evaluation. The combined use of photochemical and PK data might be efficacious for simple and fast prediction of the phototoxic potential of new drug candidates.