Effects of dihydroquinidine on in vitro and in vivo quinidine disposition.
The effects of dihydroquinidine on the metabolism of quinidine by 10,000 g supernatant fractions of rabbit and rat liver homogenates and on the disposition of quinidine in the rabbit were investigated. From Lineweaver-Burk plots, the following mean +/- S.E.M. values for V(max) and K(m) for quinidine and K(i) for dihydroquinidine for the rabbit liver preparations were obtained: 240 +/- 50 nmoles/min/g liver,0.55 +/- 0.14 mM, and 0.56 +/- 0.09 mM respectively. The corresponding values for the rat liver homogenates were 74 +/- 6 nmoles/min/g liver, 0.12 +/- 0.02 mM and 0.14 +/- 0.06 mM. From Dixon plots, the following values for K(i) for dihydroquinidine were obtained:0.54 +/- 0.09 mM for the rabbit liver preparations and 0.14 +/- 0.04 mM for the rat liver homogenates. In rabbits pretreated with dihydroquinidine for an average of 26 days, no changes in the distribution and elimination half-life values for quinidine, total body clearance, or apparent volume of drug distribution were observed when compared to the control quinidine disposition constants obtained in the same animals. As their structures suggested, the data showed that the interactions of dihydroquinidine and quinidine during drug metabolism by rabbit and rat liver 10,000 g supernatant fractions were competitive. Additionally, the affinities of dihydroquinidine and quinidine for the drug-metabolizing enzymes in these preparations were the same. The data also suggested that the small amounts of dihydroquinidine normally found in quinidine preparations probably have no significant effect on the disposition of quinidine in the body when therapeutic doses of the drug are used.
Department of Pharmaceutics, College of Pharmacy and Cardiovascular Center, The University of Nebraska Medical Center, Omaha, NE 68105, USA.
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Ueda
D000818:Animals; D001667:Binding, Competitive; D007700:Kinetics; D008297:Male; D011802:Quinidine / Q000031:analogs & derivatives* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D011802:Quinidine