Preclinical Pharmacokinetics of PDE-310, a Novel PDE4 Inhibitor

Summary: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 the pharmacokinetics of PDE-310. The 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− 6cm/s), with higher transport in the secretory direction, giving efflux ratios of 3.9 and 2.6 at 5 and 10 μΜ, respectively. In addition, the high efflux ratio and improved absorption on treatment with efflux transporter inhibitors such as verapamil and MK-571 indicated the involvement of P-gp, BCRP and MRP2 in 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, nonlinear elimination of PDE-310 was observed at the tested dose ranges (Km, 0.87 μg/mL; Vmax, 0.3 mg-h− 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.