Chemical reactivity of the naproxen acyl glucuronide and the naproxen coenzyme A thioester towards bionucleophiles.
J Pharm Biomed Anal
; 29(1-2): 7-15, 2002 Jun 20.
Article
em En
| MEDLINE
| ID: mdl-12062660
ABSTRACT
Drugs may be metabolised to reactive electrophilic species that spontaneously react with proteins. The presence of such drug-protein adducts has been associated with drug toxicity. In this study, the reactivity of the major metabolite of naproxen--the 1-beta-O-glucuronide (Nap-GlcU)--was compared to the corresponding naproxen coenzyme A (Nap-CoA) thioester. The reactivity of the two metabolites was assessed in vitro in a phosphate buffer (pH 7.4; 0.1 M) at 37 degrees C towards the model bionucleophiles glutathione and human serum albumin (HSA). The reaction between the electrophilic species (Nap-GlcU and Nap-CoA) and glutathione forming the Nap-glutathione conjugate was monitored using LC-MS-MS and LC-UV, respectively. It was shown that Nap-CoA resulted in an approximate 100-fold higher formation of Nap-glutathione conjugate than Nap-GlcU. The presence of Nap-CoA also resulted in acylated HSA with a rate and a yield that was significantly higher than reported for Nap-GlcU. In summary, the data suggest that CoA metabolites may be more reactive species than acyl glucuronides that previously have been associated with severe drug related side effects in vivo.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Química Farmacêutica
/
Anti-Inflamatórios não Esteroides
/
Naproxeno
/
Coenzima A
/
Glucuronídeos
Limite:
Humans
Idioma:
En
Revista:
J Pharm Biomed Anal
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Dinamarca