Influência do diabetes mellitus no metabolismo de fármaco marcadores de atividade dos CYP2D6 e 3A4 em ratos

Abstract

Cytochrome P450 (CYP450) and its isoforms can be regulated by exogenous and endogenous compounds and also diseases. Diabetes Mellitus (DM) is a multiple etiology syndrome resulting from a lack or inability of insulin to properly exercise its action, that can modify the CYP450 activity. This research evaluates the influence of DM on CYP2D6 and CYP3A4 isoforms activity employing metoprolol (MET) and midazolam (MDZ) as probe drugs. Male Wistar rats 200-250g, were treated with single oral dose of 20mg/kg for MET and 15 mg/kg for MDZ. Diabetes mellitus was induced by streptozotocin (50mg/kg) intravenously administered. Midazolam, metoprolol and alpha-hydroxymetoprolol were analyzed in plasma by ultraperformance liquid chromatography (column XR-ODS) coupled to a mass spectrometer. The sample preparation was perfomed using liquid-liquid extraction. Pharmacokinetics of MDZ in rats showed a significant decrease (54,01 vs 12,24 L/h/kg) of total clearance in the diabetic animals compared to control group and a significant increase (402.66 vs 1742.6 h.ng/mL) AUC0- ‡ in the diabetic group compared with the control. The DM altered the AUC0- ‡ of MET in the diabetic group compared to control (998.09 vs 348.45 h.ng/mL) followed by a significant decrease in clearance in the diabetic group (46.85 vs 17.80 L/h/kg). Since no changes in alpha- hydroxymetoprolol pharmacokinetics was observed, the increase in MET AUC0- ‡ can be explained by DM inhibition of other MET metabolization pathways. Data analysis suggests that DM inhibits CYP3A4 activity and had no effect on CYP2D6 activity