2012 年 43 巻 3 号 p. 157-164
Pilsicainide is a cationic antiarrhythmic agent that has the potential of drug-drug interactions because of P-glycoprotein (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-gp-expressing 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.
