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Biochem J ; 284 ( Pt 1): 289-95, 1992 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-1599408

RESUMEN

The formation of acyl-CoA esters of the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate and nafenopin was studied in isolated rat hepatocytes. The concentration of ciprofibroyl-CoA in the liver of ciprofibrate-treated rats was in the range of 10-30 microM. The three drugs formed acyl-CoA esters when incubated with isolated hepatocytes. Their formation was saturable and reached a plateau after 30 min incubation. Maximal intracellular concentrations of ciprofibroyl-CoA and clofibroyl-CoA (100 microM and 55 microM respectively) were attained at 0.5 mM of the free drugs in the incubation medium, whereas for nafenopin-CoA, the maximal intracellular concentration (9 microM) was reached at 1 mM-nafenopin. At low concentrations of the hypolipidaemic compounds in the incubation medium a significant proportion of the total intracellular drug was present as its acyl-CoA ester (25-35% for ciprofibrate). When isolated hepatocytes were incubated with a ciprofibrate concentration comparable with that observed in the blood of drug-treated rats (0.1 mM), ciprofibroyl-CoA attained an intracellular concentration similar to that previously observed in the liver of treated rats. The formation of ciprofibroyl-CoA by isolated rat hepatocytes was stimulated by the addition of carnitine and partially inhibited by the addition of palmitate. Further, it was shown that human liver homogenates synthesized ciprofibroyl-CoA at a rate similar to that observed for rat liver homogenates. Solubilized human platelets also formed ciprofibroyl-CoA, although at a rate two orders of magnitude lower than that of liver. The results support the view that acyl-CoA esters of hypolipidaemic peroxisome proliferators may be the pharmacologically active species of the drugs.


Asunto(s)
Plaquetas/metabolismo , Ácido Clofíbrico/análogos & derivados , Ácido Clofíbrico/farmacocinética , Lípidos/sangre , Hígado/metabolismo , Nafenopina/farmacocinética , Acilcoenzima A/metabolismo , Animales , Biotransformación , Carnitina/farmacología , Células Cultivadas , Ácido Clofíbrico/metabolismo , Ácido Clofíbrico/farmacología , Ácidos Fíbricos , Humanos , Cinética , Hígado/citología , Nafenopina/análogos & derivados , Nafenopina/metabolismo , Octoxinol , Ácido Palmítico , Ácidos Palmíticos/farmacología , Polietilenglicoles/farmacología , Ratas , Ratas Endogámicas
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