ABSTRACT
Se describe un método sensible y específico de cromatografía de alta resolución (HPCL) para el análisis en plasma humano de 3-hidroxi, 3-etil, 3-fenil propionami-da (HEPP), un nuevo anticonvulsivante. El estándar interno (2-hidroxi, 2-etil, 2-fenil acetamida HEPA) y la HEPP se extrajeron en acetonitrilo de plasma amortiguado, la extracción fue cercana al 100 por ciento respecto a la cantidad extraída de cada fármaco de solución salina amortiguada. El método consiste en HPCL en fase reversa (Lichro Spher 100 RP-18 en Lichro Cart 125-4), la fase móvil está compuesta de metanol-acetonitrilo-amortiguador de fosfatos (35/15/50 por vol) y detección ultravioleta a 200 nm. Las curvas de calibración fueron lineales y repetibles (coeficiente de correlación > 0.999). Las determinaciones de HEPP en plasma humano o en solución salina fueron lineales en el intervalo 0 - 10 µg/ml y el coeficiente de variación fue menor que 10 por ciento. HEPP es muy estable a temperatura ambiente y a 4 ºC, y puede ser cuantificada en presencia de otros antiepilépticos tales como: difenilhidantoina, clonazepam. carbamezepina y hexobarbital
Subject(s)
Anticonvulsants/chemistry , Carbamazepine/chemistry , Clonazepam/chemistry , Chromatography, Liquid/methods , Epilepsy/therapy , Phenytoin/chemistry , Hexobarbital/chemistry , Pharmacokinetics , Propionates/chemistryABSTRACT
The simultaneous administration of two or more drugs may result in interactions that increase or decrease the intended effects of one or both drugs. These interactions are often the result of induced alterations in the metabolism of the drugs. A wide variety of unrelated chemical agents are also capable of enhancing the activity of drug-metabolizing enzymea in the smooth-surfaced endoplasmic reticulum of the liver, and this accelerated metabolism alters the duration and intensity of action of a variety of pharmacological agents. Phenobarbital is a well known drug which promotes the metabolism of durgs in the liver. Some volatile or intravenous anesthetics were reported that enhance hepatic microspmal metabolism for themselves or for other drugs. Of these, Chang and Glazko (1974) reported that ketamine pretreatment did not influence the demethylation rate of drug metabolism and the liver weight in rats. However many opposite opinions have been expressed that ketamine enhanced mierosomal drug metabolism. Marietta et al (1975 and 1976) reported that the demethylating enzyme fraction of the ketamine-pretreated group was double of that of the control group in vitro. Thus we have made a study to evaluate the enhancement of drug metabolism induced by ketamine hydrochloride. Our experimental mice were divided into 4 groups, preteated with saline, phenobarbital, ketamine or carbon tetracbloride for 3 days. On the 1 st, 3 rd, 5th, 7th and 14th day after the pretreatment, we selected 10 mice randomly in each group, and hexobarbital(100mg/kg) was administered intraperitonealy. Then we evaluated the sleeping time, liver weight and microscopic findings of liver tissue. The results are as follows: 1) On the 1 st, 3 rd and 5th day after the pretreatment, the duration of hexobarbital induced hypnosis was significantly shorter in the ketamine-pretreated group than that in the control group, but not as long as that in the phenobarbital-pretreated group. 2) There was no remarkable change of the liver weight in the ketamine pretreated group. On the 1st and 3rd day after the pretreatment, liver weight was significanty increased in the phenobarbital and carbon tetrachloride pretreated groups. 3). Microscopic findings of liver showed no remarkable change in the ketamine-pretreated group, but there were significant cholestasis and hydrophic degeneration in the phenobarbital-and carbon tetrachloride-pretreated group respectively. In conclusion, it may be indicated that ketamine enhances hepatic microsomal drug metabolism because of shortening of the duration of hexobarbital-induced hypnosis.