Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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Pharmaceutical strategy for improving photostability of dacarbazine with reduced production of algogenic photodegradants
Atsushi Uchida, Hiroto Ohtake, Yukiko Suzuki, Hideyuki Sato, Yoshiki Seto, Satomi Onoue, Toshio Oguchi

Last modified: 2019-07-13


Background: Dacarbazine [5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; DTIC] is an anti-cancer drug for the treatment of metastatic malignant melanoma and soft tissue sarcoma.  DTIC may cause vascular pain as adverse effect, and 5-diazoimidazole-4-carboxamide (Diazo-IC), a photodegradant of DTIC, had been reported to strongly relate to the occurrence of vascular pain.  Aim: The present study aimed to develop a photochemically stabilized formulation of DTIC for reducing the production of Diazo-IC.  Methods: Photochemical properties of DTIC were characterized by UV-visible light spectral analysis, reactive oxygen species (ROS) assay, and photostability testing.  A pharmacokinetic study was conducted after intravenous administration of DTIC formulations (1 mg-DTIC/kg) to rats.  Results: After exposure of DTIC (1 mM) to simulated sunlight (250 W/m2) for 3 min, remaining DTIC and yielded Diazo-IC were estimated to be ca. 230 µM and 600 µM, respectively.  The addition of radical scavenger (1 mM), including L-ascorbic acid, L-cysteine (Cys), L-histidine, D-mannitol, L-tryptophan, or L-tyrosine, to DTIC (1 mM) could attenuate DTIC photoreactions, and in particular, the addition of Cys to DTIC brought ca. 34% and 86% inhibition of DTIC photodegradation and Diazo-IC photogeneration, respectively.  There were no significant differences in the calculated pharmacokinetic parameters of DTIC between DTIC and DTIC with Cys (0.67 mg/kg).  Conclusion: From these findings, the supplementary use of Cys would be an effective approach to improve the photostability of DTIC with less production of Diazo-IC.

Key words: dacarbazine; L-cysteine; photostability; reactive oxygen species; radical scavenger