Photochemically stabilized formulation of dacarbazine with reduced production of algogenic photodegradants.
Int J Pharm
; 564: 492-498, 2019 Jun 10.
Article
en En
| MEDLINE
| ID: mdl-31022505
ABSTRACT
The present study aimed to develop a photochemically stabilized formulation of dacarbazine [5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; DTIC] for reducing the production of algogenic photodegradant (5-diazoimidazole-4-carboxamide; Diazo-IC). 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 (1â¯mg-DTIC/kg) to rats. DTIC exhibited strong absorption in the UVA range, and photoirradiated DTIC exhibited marked ROS generation. Thus, DTIC had high photoreactive potential. After exposure of DTIC (1â¯mM) to simulated sunlight (250â¯W/m2) for 3â¯min, remaining DTIC and yielded Diazo-IC were estimated to be ca. 230⯵M and 600⯵M, respectively. The addition of radical scavenger (1â¯mM), including l-ascorbic acid, l-cysteine (Cys), l-histidine, D-mannitol, l-tryptophan, or l-tyrosine, to DTIC (1â¯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 (0.67â¯mg/kg). 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.
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Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos Azo
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Depuradores de Radicales Libres
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Antineoplásicos Alquilantes
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Cisteína
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Dacarbazina
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Imidazoles
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Luz
Límite:
Animals
Idioma:
En
Revista:
Int J Pharm
Año:
2019
Tipo del documento:
Article