Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.
1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5-hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml-1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.
Funck-Brentano
C
C
Department of Medicine, Vanderbilt University, Nashville, TN 37232.
Kroemer
H K
HK
Pavlou
H
H
Woosley
R L
RL
Roden
D M
DM
D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001711:Biotransformation; D004562:Electrocardiography; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011405:Propafenone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011802:Quinidine / Q000494:pharmacology*
D011405:Propafenone; C044307:5-hydroxypropafenone; D011802:Quinidine