Stereoselectivity in O-demethylation of trans tramadol in rat liver microsomes in vitro / 药学学报
Acta Pharmaceutica Sinica
;
(12): 169-174, 2002.
Artigo
em Chinês
| WPRIM
| ID: wpr-312019
ABSTRACT
<p><b>AIM</b>To study the stereoselectivity in O-demethylation of trans tramadol.</p><p><b>METHODS</b>With or without quinine and quinidine as inhibitors, rat liver microsomes were incubated in vitro with the enantiomers or the racemate of trans tramadol. The concentrations of the enantiomers of trans tramadol and O-demethyltramadol in the incubates were determined by high performance capillary electrophoresis. The O-demethylation processes were assayed by using the enzyme kinetic analysis method.</p><p><b>RESULTS</b>After incubation, the concentrations of (-)-O-demethyltramadol were higher than those of (+)-enantiomer in all rat liver microsomal incubates. Enzyme kinetic analysis showed that the Km of the formation of the enantiomers of O-demethyltramadol were similar; The Vmax and Clint of the formation of (-)-O-demethyltramadol were significantly higher than those of the formation of (+)-enantiomer. When the racemate of trans tramadol was used as the substrate, there was interaction between the two enantiomers. The Km of the formation of the enantiomers of O-demethyltramadol increased, the Vmax of the formation of (+)-O-demethyltramadol decreased, the Vmax of the formation of (-)-O-demethyltramadol increased slightly. The O-demethylation of the enantiomers of trans tramadol was shown to be inhibited competitively by quinine and quinidine. The Ki of quinine and quinidine were 1.6 and 10.8 mumol.L-1 to the formation of (-)-O-demethyltramadol, 0.8 and 3.4 mumol.L-1 to the formation of (+)-O-demethyltramadol, respectively. Furthermore, quinine and quinidine were found to have stereoselective inhibition on the formation of O-demethyltramadol, both mainly inhibited the formation of (+)-O-demethyltramadol.</p><p><b>CONCLUSION</b>The O-demethylation of trans tramadol was found to be stereoselective in rat liver microsomes in vitro, preferentially metabolized (-)-enantiomer. The stereoselectivity could be influenced by the interaction between the two enantiomers and the enzyme selective inhibitors.</p>
Texto completo:
DisponíveL
Índice:
WPRIM (Pacífico Ocidental)
Assunto principal:
Farmacologia
/
Quinidina
/
Quinina
/
Estereoisomerismo
/
Tramadol
/
Microssomos Hepáticos
/
Separação Celular
/
Ratos Sprague-Dawley
/
Analgésicos Opioides
/
Metabolismo
Limite:
Animais
Idioma:
Chinês
Revista:
Acta Pharmaceutica Sinica
Ano de publicação:
2002
Tipo de documento:
Artigo
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