Pharmacokinetics of losartan and its metabolite, EXP3174, after intravenous and oral administration of losartan to rats with streptozotocin-induced diabetes mellitus.

Abstract

The pharmacokinetics of losartan and its active metabolite, EXP3174, were investigated after intravenous and oral administration of the drug, 5 mg/kg, to control rats and streptozotocin-induced diabetes mellitus rats (SIDRs). After 1-min intravenous infusion, the mean arterial plasma concentrations and the resultant area under the plasma concentration-time curve from zero to infinity (AUC) of both losartan and EXP3174 were not significantly different between control rats and the SIDRs. However, the renal clearance (CLR) of losartan (0.181 versus 0.0815 ml/min/kg) and EXP3174 (0.0677 versus 0.0277 ml/min/kg) were significantly faster in SIDRs than in control rats due to significant increase in glomerular filtration rate. After oral administration, the mean arterial plasma concentrations and the resultant AUC of losartan (97 versus 166 micrograms min/ml) and EXP3174 (244 versus 423 micrograms min/ml) were significantly lower in SIDRs than in control rats. The absolute extent of oral bioavailability of losartan, F, (32.5 versus 55.1%) decreased considerably in SIDRs and it was possibly due to the reduced gastrointestinal absorption of losartan by gastrointestinal disorders occurring in the diabetic state. The low F in both groups of rats was at least partially due to the increase in first-pass effects. The CLR of losartan (0.207 versus 0.101 ml/min/kg) and EXP3174 (0.0615 versus 0.0196 ml/min/kg) were significantly faster in SIDRs than in control rats after oral administration of losartan.