Kinetics of microsomal metabolism of quinidine in rats
Rakhit, A.; Mico, B.
Research Communications in Chemical Pathology and Pharmacology 49(1): 109-124
1985
ISSN/ISBN: 0034-5164 PMID: 4035074 Document Number: 250728
Kinetics of in vitro metabolism of quinidine was investigated using rat liver microsomes. Quinidine elimination was capacity limited with apparent Michaelis constant (appKM) of 2.6 microM (about 1.2 mg/L) in liver microsomes from uninduced rats. Phenobarbital (PB) pretreatment caused induction of quinidine metabolism. Formation of all three metabolites important in man, 3-hydroxyquinidine, quinidine N-oxide and quinidine 10,11-dihydrodiol were PB inducible (Vmax increased). To study any direct interaction between PB and quinidine, PB was also added to the microsomal incubate and was found to decrease the rate constant for quinidine metabolism, suggesting inhibition of quinidine metabolism by PB. While, 3-hydroxyquinidine formation was inhibited (Vmax decreased and KM increased), the formation of quinidine N-oxide was activated (Vmax increased). The formation of quinidine 10,11-dihydrodiol, although a minor metabolite in rat, was also inhibited in presence of PB. It is apparent from this study that PB when administered in vivo would act as both inducer and inhibitor of quinidine metabolism.