In Vitro P-Glycoprotein-Mediated Transport of Tadalafil: A Comparison with Sildenafil

Tadalafil and sildenafil are selective inhibitors of phosphodiesterase type 5, showing marked pharmacokinetic variability in patients with pulmonary arterial hypertension. It has been reported that sildenafil is a substrate for P-glycoprotein (P-gp), but whether tadalafil is a substrate for P-gp remains to be determined. The objective of the present study was to elucidate whether tadalafil is a substrate for P-gp. Transcellular transport of sildenafil and tadalafil (5 µM each) was examined using renal epithelial LLC-PK₁ and P-gp-expressing LLC-GA5-COL150 cell monolayers. The efflux ratio of the basal to apical (B to A) transport of sildenafil to the A to B transport after 120-min incubation in LLC-GA5-COL150 cells (1.52) was significantly higher than that in LLC-PK₁ cells (0.711). The efflux ratio of the B to A transport of tadalafil to the A to B transport after 120-min incubation in LLC-GA5-COL150 cells (10.4) was significantly higher than that in LLC-PK₁ cells (1.23). In LLC-GA5-COL150 cell monolayers, the V_max and K_m values of sildenafil transport calculated from a modified Michaelis-Menten equation were 101±64 pmol/min/cm² and 112±47 µM, respectively. On the other hand, those of tadalafil transport were 13.6±4.8 pmol/min/cm² and 22.7±9.3 µM, respectively. In the presence of a P-gp inhibitor (PSC833), the B to A transport of tadalafil was decreased by 28.6% in LLC-GA5-COL150 cells, and the A to B transport of tadalafil was 6.59-fold greater than that in its absence. These results indicate that tadalafil is a substrate for P-gp.