RESUMEN
BACKGROUND: Silymarin, a hepatoprotective agent, has poor oral bioavailability. However, the current dosage form of the drug does not target the liver and inflammatory cells selectively. The aim of the present study was to develop lecithin-based carrier system of silymarin by incorporating phytosomal-liposomal approach to increase its oral bioavailability and to make it target-specific to the liver for enhanced hepatoprotection. METHODS: The formulation was prepared by film hydration method. Release of drug was assessed at pH 1.2 and 7.4. Formulation was assessed for in vitro hepatoprotection on Chang liver cells, lipopolysaccharide-induced reactive oxygen species (ROS) production by RAW 267.4 (murine macrophages), in vivo efficacy against paracetamol-induced hepatotoxicity and pharmacokinetic study by oral route in Wistar rat. RESULTS: The formulation showed maximum entrapment (55%) for a lecithin-cholesterol ratio of 6:1. Comparative release profile of formulation was better than silymarin at pH 1.2 and pH 7.4. In vitro studies showed a better hepatoprotection efficacy for formulation (one and half times) and better prevention of ROS production (ten times) compared to silymarin. In in vivo model, paracetamol showed significant hepatotoxicity in Wistar rats assessed through LFT, antioxidant markers and inflammatory markers. The formulation was found more efficacious than silymarin suspension in protecting the liver against paracetamol toxicity and the associated inflammatory conditions. The liposomal formulation yielded a three and half fold higher bioavailability of silymarin as compared with silymarin suspension. CONCLUSIONS: Incorporating the phytosomal form of silymarin in liposomal carrier system increased the oral bioavailability and showed better hepatoprotection and better anti-inflammatory effects compared with silymarin suspension.
Asunto(s)
Hepatocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Silimarina/administración & dosificación , Acetaminofén/toxicidad , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Liberación de Fármacos , Hepatocitos/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Lipopolisacáridos/farmacología , Liposomas , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacocinética , Ratas , Ratas Wistar , Silibina , Silimarina/farmacocinéticaRESUMEN
Twenty four Wistar strain albino rats were used for the investigations. Lecithin 50 and 100 mg/kg b wt was administered for 1 week by oral route. Liver damage was induced by intra peritoneal administration of 400 mg/kg b wt d-galactosamine on the last day. At the end of the study animals were sacrificed and liver enzyme levels, histopathology, mitochondrial integrity, expression of p53, Bax and Bcl-2 mRNA levels were studied. Increases in the liver enzyme levels by d-GalN were significantly inhibited by pretreatment with lecithin. Histopathological observation further confirmed the hepatoprotective effect of lecithin. In addition, the disruption of mitochondrial membrane, up regulation of Bax and down regulation of Bcl-2 mRNA levels in the liver of d-GalN intoxicated rats were effectively prevented by pretreatment with lecithin. The results of the present study validate our conviction that d-GalN causes hepatic damage via mitochondrial pathway involving Bax and Bcl-2.
RESUMEN
Aim of the study was to investigate the methanol and aqueous extracts of heartwood of C. sappan for its hepatoprotective activity against CCl4 induced toxicity in freshly isolated rat hepatocytes and animals. Freshly isolated rat hepatocytes were exposed to CCl4 (1%) along with/without various concentrations of methanolic and aqueous extract of C. sappan (1000-800 microg/ml) and the levels of selected liver enzymes were estimated. Antihepatotoxic effect of methanolic extract was observed in freshly isolated rat hepatocytes at concentrations 1000-800 microg/ml and was found to be similar to that of standard drug silymarin. Wistar strain albino rat model was used for the investigation of in vivo hepatoprotective properties of aqueous and methanolic extract of C. sappan (100 and 200 mg/kg body weight). Liver damage was induced by ip administration of CCl4 (30%) suspended in olive oil (1 ml/kg body weight). Both the tested extracts showed potent hepatoprotective activity at 200 mg/kg body weight test dose which was comparable with that of the standard silymarin used in similar test dose. The methanolic and aqueous extract was able to restore the biochemical levels to normal which were altered due to CCl4 intoxication in freshly isolated rat hepatocytes and also in animals.