EFFECT OF EXPERIMENTAL RENAL-FAILURE ON THE DISPOSITION KINETICS OF L-PROPRANOLOL IN RATS

  • 1 January 1983
    • journal article
    • research article
    • Vol. 227  (2) , 295-301
Abstract
The effect of uranyl nitrate-induced renal failure on the pharmacokinetics of the levo-isomer of propranolol [an autonomic antihypertensive] in rats ws investigated. The serum clearance of an i.v. dose of propranolol (1.5 mg/kg) in normal animals approached hepatic blood flow, suggesting that the systemic clearance of the drug is rate-limited by blood flow to the liver. Extensive 1st-pass metabolism was observed after oral administration of l-propranolol. The system availability of a 6 mg/kg oral dose of l-propranolol was only 7%. Renal failure had no apparent effect on the distribution and elimination of i.v. administered l-propranolol. The area under the serum drug concentration time curve after oral administration was increased from 6.95 to 19.3 .mu.g .cntdot. min/ml, which corresponded to a 2.5-fold increase in the systemic availability of l-propranolol (from 7 to 18%). The gastrointestinal absorption of l-propranolol, as assesed by comparing the urinary recovery of radioactivity after i.v. and oral administration of l-[3H]propranol, was complete in normal animals. An increase in the extent of absorption of l-propranolol in renal failure cannot be offered as a cause of increased systemic availability. Neither the in vitro nor the in vivo serum protein binding of l-propranolol differed between renal failure and control animals. The intrinsic metabolic clearance of unbound l-propranolol in renal failure rats is estimated to be about 60% lower than that in control rats. Evidently the increase in propranolol serum concentration after oral administration of the drug to uremic patients is due to decreased presystemic biotransformation of the drug.