RESUMEN
The effects of the Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the cardioselective beta 1-adrenergic blocking agent atenolol (AT) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two hours after single oral administration, atenolol (150 mg/kg) did not change hexobarbital sleeping time, while nifedipine (50 mg/kg) and diltiazem (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadministration of atenolol with diltiazem or with nifedipine significantly prolonged hexobarbital sleep by 205 and 283%, respectively. Administered alone, atenolol decreased the ethylmorphine-N-demethylase (EMND) activity, but the amidopyrine-N-demethylase (APND) activity was not changed in any of the treated groups. Atenolol and nifedipine significantly increased aniline-4-hydroxylase (AH) activity and this effect was also observed with the combinations AT + NF and AT + DL. The NADPH cytochrome P-450 reductase activity was significantly decreased by nifedipine and diltiazem. Only nifedipine increased the total content of cytochrome P-450 (by 23.8%). Atenolol and diltiazem tended to increase the content of cytochrome b5 which was increased by nifedipine by 97.6%. The same effect was observed with the combinations AT + NF and AT + DL. The results suggest that NF, AT + NF and AT + DL produced the manifested changes in hepatic oxidative metabolism. The decreased EMND activity by atenolol, however, and the prolongation of hexobarbital sleeping time by nifedipine, diltiazem and their coadministration with atenolol did not correlate with enhanced microsomal P-450 and b5 content.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Hígado/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Oxidorreductasas/efectos de los fármacos , Aminopirina N-Demetilasa/efectos de los fármacos , Aminopirina N-Demetilasa/metabolismo , Anilina Hidroxilasa/efectos de los fármacos , Anilina Hidroxilasa/metabolismo , Animales , Atenolol/administración & dosificación , Atenolol/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos b5/efectos de los fármacos , Citocromos b5/metabolismo , Diltiazem/farmacología , Quimioterapia Combinada , Etilmorfina-N-Demetilasa/efectos de los fármacos , Etilmorfina-N-Demetilasa/metabolismo , Hexobarbital/farmacología , Hipnóticos y Sedantes/farmacología , Hígado/enzimología , Masculino , Microsomas Hepáticos/enzimología , NADPH-Ferrihemoproteína Reductasa/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/metabolismo , Nifedipino/farmacología , Oxidorreductasas/metabolismo , Ratas , Ratas WistarRESUMEN
The effects of two Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the nonselective beta-adrenergic blocking agent propranolol (PR) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two h after single oral administration PR (50 mg/kg) did not change HB sleeping time, while NF (50 mg/kg) and DL (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadmistration of PR with DL or with NF significantly prolonged HB sleep by 240.7 and 129%, respectively. Only NF increased aniline 4-hidroxylase (AH) activity (by 92%) and the total P-450 content (by 24%). PR and NF increased cytochrome b5 content and this effect was also observed with the combinations PR + NF (by 109%) and PR + DL (by 102%). The NADPH cytochrome P-450 reductase activity was significantly decreased by NF and DL and after their combination with PR. The ethymorphine-N-demethylase (EMND) and amidopyrine-N-demethylase (APND) activities were not changed. The effects of PR, NF and DL administrated alone or in combination on liver oxidative metabolism are considered as possible mechanisms of drug interactions.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Hígado/efectos de los fármacos , Propranolol/farmacología , Aminopirina N-Demetilasa/efectos de los fármacos , Aminopirina N-Demetilasa/metabolismo , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos b5/efectos de los fármacos , Citocromos b5/metabolismo , Diltiazem/farmacología , Etilmorfina-N-Demetilasa/efectos de los fármacos , Etilmorfina-N-Demetilasa/metabolismo , Hexobarbital/farmacología , Hipnóticos y Sedantes/farmacología , Hígado/enzimología , Masculino , NADPH-Ferrihemoproteína Reductasa/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/metabolismo , Nifedipino/farmacología , Ratas , Ratas Wistar , Sueño/efectos de los fármacosRESUMEN
Increase of N-demethylase and antioxidant activities and decrease of amount of hydroperoxides were observed in liver of rats after intragastric administration of Undevit (1/8 dragee/rats/day, 5 times a week during 2 months). Combination of Undevit with Cordiamin (5 mg/rat/day) resulted in augmentation of cytochromes P-450 and b5 content and activities of their reductases, velocity of amidopyrine and ethylmorphine N-demethylation and oxidation of HADPH. Activities of UDP-glucuronyltransferase, glutathionetransferase and hydrophobity of microsomal membranes were also increased. Antioxidant activity was increased and amount of hydroperoxides in liver microsomes and homogenates and in plasma was decreased in greater degree after administration of combination two compounds than after administration of Undevit alone.