RESUMEN
1. SC-52151, an HIV protease inhibitor, is mainly metabolized by CYP3A4 and is poorly bioavailable after oral administration. After i.v. administration of SC-52151 to the female beagle dog (2.5 mg/kg), SC-52151 was rapidly eliminated in plasma with an elimination half-life of about 1 h, a plasma clearance of 44 ml/min/kg and an apparent steady-state volume distribution of 2.2 litre/kg. The high value of plasma clearance of SC-52151 suggests an extensive hepatic first-pass metabolism since SC-52151 is highly protein bound and does not partition itself into red blood cells. 2. The extensive hepatic first-pass metabolism was reduced by coadministration of a CYP3A4 inhibitor, ketoconazole. 3. Dogs were dosed daily with ketoconazole at dose of 100 mg ketoconazole per dog (approximately 10 mg/kg) for 5 days prior to the initiation of coadministration of SC-52151 for 15 days. The doses used for SC-52151 was 0, 60 and 120 mg SC-52151/kg/day (divided t.i.d., 8-h dosing interval). Coadministration of ketoconazole improved the bioavailability of SC-52151 from 4.1 to 9.6% and also improved the Cmax of SC-52151 from 0.41 to 0.83 microgram/ml. 4. Although the absolute bioavailability of SC-52151 was still low (approximately 10%), the Cmax and AUC achieved in this study were satisfactory for conducting chronic toxicology studies. No toxicity associated with the coadministration of ketoconazole was evident. Results from this study suggest that coadministration of ketoconazole might be a practical approach to increase the exposure of SC-52151 in both preclinical and clinical studies.
Asunto(s)
Antifúngicos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Inhibidores de la Proteasa del VIH/farmacocinética , Isoenzimas/antagonistas & inhibidores , Cetoconazol/farmacocinética , Urea/análogos & derivados , Administración Oral , Animales , Antifúngicos/toxicidad , Disponibilidad Biológica , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Sinergismo Farmacológico , Inhibidores Enzimáticos/toxicidad , Femenino , Inhibidores de la Proteasa del VIH/toxicidad , Semivida , Inyecciones Intravenosas , Cetoconazol/toxicidad , Tasa de Depuración Metabólica , Urea/farmacocinética , Urea/toxicidadRESUMEN
SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.
Asunto(s)
Butadienos , Enfermedades Intestinales/inducido químicamente , Metilcelulosa/análogos & derivados , Misoprostol , Misoprostol/administración & dosificación , Polímeros , Gastropatías/inducido químicamente , Animales , Antiácidos/farmacología , Aspirina/toxicidad , Disponibilidad Biológica , Depresión Química , Diarrea/inducido químicamente , Perros , Portadores de Fármacos , Etanol/toxicidad , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Derivados de la Hipromelosa , Indometacina/toxicidad , Enfermedades Intestinales/prevención & control , Masculino , Misoprostol/farmacocinética , Misoprostol/toxicidad , Ratas , Ratas Endogámicas , Gastropatías/prevención & controlRESUMEN
Male Sprague-Dawley rats were given single i.p. injections of 1,3-bis(2-chloroethyl)-1-Nitrosourea (BCNU) to investigate changes in hepatic microsomal cytochrome P-450 content and metabolic activity. On day 14 after treatment (20 mg/kg), cytochrome P-450 content had decreased by approximately 25% and ethylmorphine N-demethylase activity (nmol product/nmol P-450/min) had decreased by 36%. In contrast, ethylmorphine O-deethylase and 7-ethoxycoumarin O-deethylase activities were not significantly decreased by BCNU treatment. Hepatic delta-aminolevulinic acid synthetase activity was only 60% of control values, and microsomal heme oxygenase activity was slightly but not statistically elevated. Cytochrome P-450 content in control and BCNU-treated rats increased in a similar manner after phenobarbital or beta-naphthoflavone induction. Electrophoretic analysis of cytochrome P-450 proteins isolated from hepatic endoplasmic reticular membranes of treated and control rats suggested that alterations in these proteins occurred in BCNU-treated rats. These changes in cytochrome P-450 content and activity are very similar to those reported in isolated systems exposed to bile acids or in rats with experimentally produced cholestasis. BCNU has been shown to produce cholestasis, which precedes its effects on microsomal mixed-function oxygenase activity. Thus, the delayed effects of BCNU on microsomal drug metabolism are probably secondary to its interference with bile formation.
Asunto(s)
Carmustina/farmacología , Colestasis/inducido químicamente , Sistema Enzimático del Citocromo P-450/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Oxigenasas de Función Mixta/metabolismo , Animales , Benzoflavonas/farmacología , Colestasis/enzimología , Electroforesis Discontinua , Retículo Endoplásmico/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Microsomas Hepáticos/enzimología , Peso Molecular , Tamaño de los Órganos/efectos de los fármacos , Fenobarbital/farmacología , Ratas , Ratas Endogámicas , beta-naftoflavonaRESUMEN
The N-demethylation and O-deethylation of ethylmorphine by cytochrome P-450 are simultaneously measured using high-performance liquid chromatography. All the metabolites and the substrate are extracted from the enzymatic incubation mixture with isopropanol-methylene chloride (20:80) containing 6.0 micrograms/ml codeine sulfate as an internal standard. Separation of the compounds is achieved on a C18 reversed-phase column using a mobile phase of 1% acetic acid--acetonitrile (85:15) with 1-hexanesulfonic acid as a counter-ion. Total run time is 12 min at a flow-rate of 2.0 ml/min and 144 bar. Assay of ethylmorphine N-demethylase and O-deethylase activities in rat liver microsomes revealed close agreement between this method and conventional ones. N-Demethylation was found to greatly exceed O-deethylation in liver microsomes from either control or phenobarbital-treated rats confirming results from other laboratories. This method can also be used to measure the N- and O-demethylation of codeine.