Lack of contribution of P-glycoprotein-mediated transport to renal excretion of pilsicainide in humans

Pilsicainide is a cationic antiarrhythmic agent that has the potential of drug-drug interactions because of Pglycoprotein(P-gp)-mediated transport and organic cation transport of the drug in renal tubules, We evaluated the contribution of P-gp-mediated transport to renal clearance of pilsicainide in humans. A pharmacokinetic study conducted in 8 healthy female subjects (aged 29±4 years body weight 49.8±5.2 kg) showed that verapamil (40 mg given three times a day), a potent P.gp inhibitor, did not significantly affect the renal clearance (pilsicainide alone : 224 ± 34 versus pilsicainide + verapamil : 216 ± 42 mL/min) or net renal clearance by tubular secretion (pilsicainide alone : 155 ± 31 versus pilsicainide + verapamil : 148 ± 35 mL/min) of pilsicainide after a single oral dose (50 mg). Using in vitro studies. pilsicainide stimulated little P.gp ATPase activity in human P-gpexpressing cell membranes. In addition, no concentration dependence was observed in the transcellular basolateral to apical transport of pilsicainide, and the P.gp substrates doxorubicin and vinblastine did not competitively inhibit pilsicainide transport in human P-gp-expressing LLC-GA5-COL150 cells. In conclusion, our results suggest that P-gp-mediated transport has minimal or no contribution to renal tubular secretion of pilsicainide in humans.