Pharmacokinetics of l-propranolol during repetitive dosing in normal and uranyl nitrate-induced renal failure rats

Abstract

The effect of experimental renal failure on the intravenous and oral pharmacokinetics of l-propranolol was studied in rats. Renal failure was induced by a single intravenous injection of uranyl nitrate (5 mg/kg). Pharmacokinetic studies were carried out on the fifth day after injection of the renal toxin (renal failure group) or saline (control group). Serum concentration time course of l-propranolol was characterized after a single intravenous or oral dose as well as after five consecutive doses of the drug given at 3-hr intervals. During repetitive intravenous drug administration, steady state was reached by the second dose, i.e., within 6 hr after initiation of repetitive dosing. No significant difference in the serum concentration time course of l-propranolol was observed between control and renal failure animals. In both groups the AUC over the steady-state dosing interval was on the average 21-27% higher than the AUC after a single dose, indicating a slight decrease in the systemic clearance of l-propranolol during repetitive intravenous drug administration. An approximately two- to three-fold higher serum l-propranolol concentration was observed in renal failure animals as compared to the normal controls after both single or repetitive oral dosing. The apparent reduction in oral clearance probably reflected an inhibition of the hepatic first-pass metabolism of l-propranolol in the renal failure rat. An unexpectedly high and protracted accumulation of serum l-propranolol concentration was observed during repetitive oral drug administration. Continuing accumulation was still evident after the fifth oral dose, i.e., a period of 15 hr or approximately 10 half-lives. The mean AUC over the last dosing interval was 32.0 and 17.8 times higher than the predicted steady-state estimate based on single oral dose data for control and renal failure rats, respectively. The substantial reduction in the oral clearance during repetitive drug administration may be due to an auto-inhibition of l-propranolol metabolism.