Genetically‐determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

Abstract

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-' (P < 0.001), decreased 5-hydroxypropafenone concentrations from 242 ± 196 to 125 ± 97 ng ml-' (P < 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 contrast, 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.

Clinical Pharmacokinetics of Propafenone

“…Despite the changes in plasma concentrations of the 2 substances, no significant change in heart rate, QRS, PR or QTc intervals was noted. No significant interaction was observed in those with the poor metaboliser phenotype (Funck-Brentano et al 1989). …”

Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers

“…Therefore propafenone is likely to have a pharmacokinetic interaction with CYP2D6 inhibitors. A previous study in white subjects found that low‐dose quinidine, a potent inhibitor of CYP2D6, increased total propafenone plasma concentration in patients with arrhythmia but caused no changes in QRS interval 13 . Another pharmacodynamic study showed that low‐dose quinidine significantly increased the extent of propafenone‐induced β‐blockade 14 .…”

Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

“…Due to their clinical sensitivity and apparent dependency on CYP2D6 in the metabolism (table 3), care should be paid with respect to coadministration of CYP2D6 inhibitors. The same applies for propafenone, where an almost 3-fold increase in exposure was reported during concurrent use of quinidine [61]. Regarding encainide, whose principal activity is mediated through the metabolite produced by CYP2D6, two studies with quinidine had contradictory results (table 8).…”