RESUMO
Two structural analogues of D-homo-8-azasteroids, both an immunostimulant and an immunodepressant, are inductors of the liver cytochrome P-450 in animals. This capability was shown by means of both a decrease of the hexenal sleep duration in the pharmacological test and an increase of the quantity of cytochrome P-450 and the rate of N-demethylation of aminopyrine in the biochemical assays.
Assuntos
Adjuvantes Imunológicos/farmacologia , Azasteroides/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Microssomos Hepáticos/efeitos dos fármacos , Esteroides Heterocíclicos/farmacologia , Animais , Ciclofosfamida/farmacologia , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Hexobarbital , Imunossupressores/farmacologia , Masculino , Camundongos , Microssomos Hepáticos/enzimologia , Fenobarbital/farmacologia , Ratos , Sono/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The pharmacokinetic investigation and the study of metabolism of an immunostimulator of 8-azasteroid series were performed on a single-compartment model. The main pharmacokinetic parameters of the immunomodulator in mice were established using different routes of administration. The maximal accumulation of tritium-labeled 8-azasteroid was recorded in the kidneys, liver and lung. The character of distribution changes with time. The half-life period is in the range of from 0.69 to 1.4 hours at different routes of administration. The total clearance is 0.49 ml/min, the area under the pharmacokinetic curve--3.8-8.1 micrograms/h/ml. On the model of the monooxygenase cytochrome P-450-containing system of the liver microsomes there was confirmed the formation of two metabolites preliminarily isolated from the mouse urine. By the character of resorption, distribution, elimination this 8-azasteroid immunoactivator is close to the agents of glucocorticoid series.
Assuntos
Adjuvantes Imunológicos/farmacocinética , Azasteroides/farmacocinética , Esteroides Heterocíclicos/farmacocinética , Adjuvantes Imunológicos/administração & dosagem , Animais , Azasteroides/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Meia-Vida , Hidroxilação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Fatores de Tempo , Distribuição Tecidual , TrítioRESUMO
The kinetics of oxidation of 15 alpha-methyl-8-aza-16-oxagona-1,3,5(10),13-tetraen-17-on with rat liver microsomal cytochrome P-450 was investigated. The kinetic parameters, Km and Vmax, of the oxidation reaction were found to be equal to 1,3 X 10(-4) M and 4.0 X 10(-7) M X s-1, respectively. Using thin-layer chromatography, mass-spectrometry, PMR-spectroscopy and reciprocal synthesis, it was shown that 3-hydroxy-15 alpha-methyl-8-aza-16-oxagona-1,3,5(10), 13-tetraen-17-on is the main reaction product.
