Kinetic analysis of propranolol-induced impairment of its own metabolism in rats.
The effect of repetitive oral administration of propranolol (100 mg kg-1 day-1, 5 days) on the kinetics of liver microsomal propranolol metabolism was investigated in the rat. Vmax values of the high-affinity phase for biphasic kinetics of propranolol 4- and 5-hydroxylase activities were decreased by propranolol pretreatment, while those of the low-affinity phase were unchanged. The Vmax value of monophasic 7-hydroxylase activity was also decreased. On the other hand, the Vmax value of N-desisopropylase activity in the propranolol-treated rats was increased more than 2-fold compared with non-treated (control) rats, resulting in a change from monophasic in control rats to biphasic kinetics in propranolol-treated rats. These findings indicate that repetitive administration of propranolol selectively impairs a CYP2D isozyme that is involved in the high-affinity phases for propranolol ring-hydroxylations.
Kagimoto
N
N
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Masubuchi
Y
Y
Fujita
S
S
Narimatsu
S
S
Suzuki
T
T
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D006899:Mixed Function Oxygenases