Preclinical Pharmacokinetics of PDE-310, a Novel PDE4 Inhibitor

초록

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, similar to 20 x 10(-6)cm/s), with higher transport in the secretory direction, giving efflux ratios of 3.9 and 2.6 at 5 and 10 mu M, 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 (K-m, 0.87 mu g/mL; V-max, 0.3 mg.h(-1).kg(-1)). Following oral PDE-310 administration, dose-normalized AUC and T-max 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.

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