Kinetic Studies of Dose-Dependent Metabolism of Alprenolol: In Vitro and In Vivo Studies in Different Species

Abstract 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 μM. In all species the rate of aromatic hydroxylation reached a plateu above 50 μM 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 μM and 1.3 μM respectively, showed no concentration dependency in contrast to the rat (Km₁ = 0.20 μM, Km₂ = 26 μM) and the dog (Km₁ = 0.78 μM, Km₂ = 66 μM). The apparent Km-value of 0.20 μM for aromatic hydroxylation in the rat seemed to be of the same order of magnitude as reported spectral dissociation constant (Ks = 0.34 μM). In vivo experiments in the rat by oral administration of 7-700 μmol/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.