In vitro metabolism of 1,3-dioxane, 1,3-oxathiolane, and 1,3-dithiane derivatives of theophylline: a structure-metabolism correlation study.
Farmaco
; 48(5): 677-90, 1993 May.
Article
em En
| MEDLINE
| ID: mdl-8343213
ABSTRACT
Correlation between structure and metabolism was studied within a series of cyclic acetal and thioacetal theophylline derivatives. All the compounds showed marked regioselectivity in in vitro metabolism, the metabolites arising only from 7-cycloalkyl side chain transformation. The 1,3-dioxane derivative, besides N-dealkylation to theophylline, underwent enzymatic ring cleavage, through the oxidation of the acetal carbon and subsequent rearrangement. Thus the acetal group was converted enzymatically to an ester. A similar transformation, catalyzed by cytochrome P450-dependent monooxygenases, was previously found for the 1,3-dioxolane ring of doxophylline. The cyclic thioacetal derivatives (i.e. 1,3-oxathiolane and 1,3-dithiane) were not cleaved during oxidative metabolism. The metabolites arise only from the oxidation of the sulfur atom, the major nucleophilic center in the molecule. No N-dealkylation to theophylline was observed. Enzymatic sulfoxidation proceeded diastereoselectively in both the 1,3-oxathiolane and 1,3-dithiane rings, the trans isomers being the major ones with a ratio trans cis 7525 and 6040 respectively. The sulfoxides were stable to hydrolysis and were not further metabolized. Neither disulfoxides nor sulfones were detected in the incubations.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Sulfidrila
/
Teofilina
/
Microssomos Hepáticos
/
Dioxanos
Limite:
Animals
Idioma:
En
Revista:
Farmaco
Ano de publicação:
1993
Tipo de documento:
Article