抄録
A novel phosphodiesterase-4 inhibitor, 2-aryl-7(3',4'-dialkoxyphenyl)-pyrazolo[1,5-alpha] pyrimidine (PDE-310), has been synthesized for the treatment of respiratory diseases. We conducted in vitro and in vivo studies to characterize pharmacokinetics of PDE-310. High liver microsomal stability and low inhibitory potency against CYP isoforms of PDE-310 suggested a low first-pass effect and high bioavailability. PDE-310 exhibited high Caco-2 cell permeability in the absorptive direction (apparent permeability coefficients, ~20 × 10−6 cm/s), with higher transport in the secretory direction, giving efflux ratios of 3.9 and 2.6 at 5 and 10 µM, respectively. In addition, high efflux ratio and improved absorption by the treatments of efflux transporters inhibitors such as verapamil and MK-571 indicated the involvements of P-gp, BCRP and MRP2 in the intestinal transport. PDE-310 bound strongly to human plasma proteins, whereas significantly more PDE-310 (27-34%) was free in rat plasma. Following intravenous administration, non linear elimination of PDE-310 was observed at the tested dose ranges (Km, 0.87 µg/mL; Vmax, 0.3 mg•hr−1•kg−1). Following oral PDE-310 administration, dose-normalized AUC and Tmax increased significantly in a dose-dependent manner. PDE-310 exhibited high oral bioavailability (>70%) and was distributed well to various tissues except brain and testis.
