Pharmacokinetics and metabolism of the pharmacologically active 4'-hydroxylated metabolite of propranolol in the dog.

The disposition of 4'-hydroxypropranolol (HOP) was determined after iv administration to dogs (2 mg/kg; N = 5) and the pharmacokinetic parameters were calculated from plasma measurements. The clearance of HOP, 66 +/- 6 ml/min/kg (mean +/- SE), was considerably higher than that of propranolol previously determined, suggesting extrahepatic as well as hepatic clearance of HOP. The plasma half-life of HOP, 77 +/- 6 min, was shorter than that of propranolol. Although HOP is considerably less lipophilic than propranolol, its volume of distribution, 6.4 +/- 0.8 liter/kg, surprisingly, was larger. Like propranolol, HOP appeared to be cleared entirely by metabolism. Whereas propranolol is metabolized mainly by oxidation, HOP was metabolized to sulfate (HOPS) and glucuronic acid (HOPG) conjugates. The plasma half-lives of these conjugates were 2 to 3 times longer than for HOP, reflecting a slow, continuous formation from HOP. This was established for HOPS by iv administration of synthetic HOPS. Morover, after HOP administration both formation and renal clearance of HOPS were stereoselective in favor of the R-enantiomer. In summary, the main conclusion of this study is that the large volume of distribution as well as high clearance through sulfation and glucuronidation may explain the low plasma HOP levels observed during propranolol therapy.