Abstract

Propranolol is an adrenergic beta receptor antagonist whose kinetics is complicated by dose-dependency, formation of active metabolites and stereoselective availability. To get some insight of the possible metabolic factors behind this, we have incubated the two optical isomers (R)- and (S)-propranolol with human and dog liver microsomes. Propranolol and its oxidized metabolites 4-hydroxypropranolol (4-OH-P) and N-desisopropylpropranolol (nor-P) were analyzed using high-performance liquid chromatography and fluorometric detection. The oxidation rates varied markedly between human livers. Most of metabolized propranolol was recovered as 4-OH-P and nor-P and more propranolol was oxidized than glucuronidated. Formation rates of 4-OH-P and nor-P were approximately half-maximal at propranolol concentrations than can occur in the liver in vivo. The ratio between formation of these metabolites varied markedly between livers. Human livers formed 4-OH-P and nor-P most rapidly from (R)-propranolol, whereas dog livers formed 4-OH-P most rapidly from (S)-propranolol. We suggest that the interindividual differences in the capacity of the livers to metabolize propranolol largely should contribute to the kinetic variations observed between patients in vivo and the gradual saturation of 4-hydroxylation and N-desisopropylation of propranolol are likely to contribute to the dose-dependent kinetics.