Flecainide pharmacokinetics are influenced by CYP3A5 and ABCB1 polymorphisms

Abstract

<b>Objective:</b> Flecainide is thought to be metabolized by cytochrome P450 (CYP) 2D6 but it interacts with drugs such as amiodarone which may suggest other pathways are involved. We retrospectively examined the effects of common polymorphisms in CYP2D6, CYP3A5 and ABCB1 on flecainide pharmacokinetics and ECG changes in 15 healthy male Chinese subjects taking part in bioequivalence studies with flecainide 100 mg.

<b>Methods:</b> The CYP2D6 *5 and *10, CYP3A5*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were examined for associations with flecainide pharmacokinetic and pharmacodynamic (ECG intervals at 3 and 12 hours post dosing) parameters.

<b>Results:</b> There was no significant effect of CYP2D6 polymorphisms, but subjects with CYP3A5*3/*3 genotype (n = 8) had increased mean AUC_o–∞ and longer median T_max compared to those with one or two copies of wild-type alleles [3709.4±749.6 vs. 2904.3±367.1 ng·h/ml; 2.0 (1.5, 2.4) vs. 1.0 (1.0, 1.5) h, p < 0.05 for both]. Subjects with ABCB1 1236C/C or C/T genotype (n = 8) also had increased AUC_o–∞ and greater PR interval change at 12 hours than those with 1236T/T genotype (3743.5±401.8 vs. 2919.3±794.7 ng·h/ml; 10.0±11.6% vs. 0.3±2.6%, p < 0.05 for both). The effects of CYP3A5 and ABCB1 polymorphisms appear to be independent and additive as subjects with CYP3A5*3*3 + ABCB1 1236C/C or C/T had highest systemic exposure to flecainide whereas subjects with CYP3A5*1/*1 or *1/*3 + ABCB1 1236T/T had lowest values (3874.4.3±308.3 vs 2771.8±175.8 ng·h/ml).

<b>Conclusion:</b> The present study showed that CYP3A5*3 and ABCB1 1236C>T polymorphisms influenced flecainide pharmacokinetics. This has implications for drug interactions with other drugs which modulate these pathways.