RESUMEN
1. The effect of age and obesity on the pharmacokinetics (PK), hepatic blood flow (HBF) and liver metabolism of 10 compounds was determined in rats. The animals fed a high-fat diet were defined as the diet-induced obese (DIO) group, while the animals that were aged similar to the DIO rats but not fed with high-fat diet were called the age-matched (AM) group. 2. The clearance (CL) values of high CL compounds (CL > 50 mL/min/kg, namely propranolol, diazepam, phenytoin, ethinylestradiol, lorcaserin and fenfluramine) decreased significantly (1.5- to 6-fold) in DIO and AM rats as compared to lean rats, while there was no clear trend for change in CL for the low-to-moderate CL compounds (CL < 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (t1/2) only for phenytoin. The body weight normalized liver weights and HBF of AM and DIO rats were found to be 2- to 3-fold lower than in lean rats. 3. Our findings suggest that age, and diet to a lesser extent, can reduce HBF and body normalized liver weights and, hence, also reduce CL values for high CL compounds in rats.
Asunto(s)
Envejecimiento/fisiología , Hígado/irrigación sanguínea , Hígado/metabolismo , Obesidad/metabolismo , Animales , Células Cultivadas , Grasas de la Dieta/efectos adversos , Semivida , Hepatocitos/metabolismo , Obesidad/etiología , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: Signal transducer and activator of transcription 3 (STAT3) has been shown to be constitutively active in approximately 50% of patients with acute myeloid leukemia and is associated with worse outcome. Arsenic trioxide (ATO) synergizes with the heat shock protein (HSP) 90 inhibitor, 17-DMAG, to down-regulate STAT3 activity. However, both agents up-regulate HSP70, an anti-apoptotic protein. We therefore examined whether down-regulating HSP70 with short interference (si) RNA will affect ATO and 17-DMAG effects on constitutive STAT3 activity. EXPERIMENTAL DESIGN: A semi-mechanistic pharmacodynamic model was used to characterize concentration-effect relationships of ATO and 17-DMAG effects on constitutive STAT3 activity and HSP70 expression with or without siRNA against HSP70 in a cell line model. RESULTS: Treatment with siRNA for HSP70 resulted in a stronger degree of synergism on down-regulation of STAT3 activity by ATO and 17-DMAG. However, treatment with siRNA for HSP70 resulted in less synergism on up-regulation of HSP70 by the two drugs. CONCLUSIONS: Down-regulation of HSP70 improves ATO and 17-DMAG effects on constitutive STAT3 activity. These results further provide a basis for studying the combined role of ATO with a HSP90 inhibitor such as 17-DMAG in AML with constitutive STAT3 activity.