Kinetic studies of dose-dependent metabolism of alprenolol: in vitro and in vivo studies in different species.

Kinetic studies of the metabolism of alprenolol were performed with isolated microsomes from the rat, guinea-pig, dog and man at an initial substrate concentration of 0.17--150 micrometer. In all species the rate of aromatic hydroxylation reached a plateu above 50 micrometer of alprenolol in contrast to the rate of desisopropylation, where consistent saturation level was not obtained. The Km-values for the aromatic hydroxylation in the guinea-pig and man, 2,7 micrometer and 1.3 micrometer respectively, showed no concentration dependency in contrast to the rat (Km1 = 0.20 micrometer, Km2 = 26 micrometer) and the dog (Km1 = 0.78 micrometer, Km2 = 66 micrometer). The apparent Km-value of 0.20 micrometer for aromatic hydroxylation in the rat seemed to be of the same order of magnitude as reported spectral dissociation constant (Ks = 0.34 micrometer). In vivo experiments in the rat by oral administration of 7--700 mu mol/kg demonstrated a dose-dependent presystemic elimination of alprenolol. The urinary excretion of hydroxy-alprenolol was significantly lower after the highest dose. It is proposed, that the saturation of the aromatic hydroxylation, catalyzed by a high affinity site or subspecies of cytochrome P-450 with a low capacity, contributes to the dose-dependent kinetics in vivo.