The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide.

The pharmacokinetics and urinary excretion of flecainide (50 mg administered orally) were investigated in five extensive metabolizers (EMs) and five poor metabolizers (PMs) of the sparteine/debrisoquin type of polymorphism under conditions of controlled urinary pH. Flecainide disposition was altered in the PMs. The AUC was higher (1462 +/- 407 versus 860 +/- 256 hr ng/ml), the elimination half-life prolonged (11.8 versus 6.8 hours), and the amount excreted in the urine was higher (26.7 +/- 7.2 versus 15.4 +/- 1.3 mg) in PMs compared with EMs (p less than 0.05). Oral clearance of flecainide was reduced (p less than 0.019) in PMs (600 +/- 139 versus 1041 +/- 307 ml/min in EMs). The renal clearance was similar (p greater than 0.05) in PMs (308 +/- 70 ml/min) and EMs (315 +/- 69 ml/min) and, consequently, PMs had a lower (p less than 0.008) metabolic clearance of flecainide (292 +/- 136 versus 726 +/- 240 ml/min in EMs). Under conditions of uncontrolled urinary flow and pH, renal excretion of flecainide will be reduced and the difference in disposition will be greater. In PMs with renal impairment, accumulation of flecainide to very high serum concentrations may be anticipated, and this may result in proarrhythmic effects.