title: Preclinical pharmacokinetics of PDE-310, a novel PDE4 inhibitor.
abstract: 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(-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, 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 µg/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.
authors.affiliation: Drug Discovery Platform Technology Team, Division of Bio-organic Science, Korea Research Institute of Chemical Technology, Republic of Korea.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Hyeong Jin
authors.initials: HJ
authors.lastname: Rho
authors.forename: Jong Shik
authors.initials: JS
authors.lastname: Park
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Byung Hoi
authors.initials: BH
authors.lastname: Lee
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Seo
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Jeon
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Kwon
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010539:Permeability; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011422:Propionates / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D058988:Phosphodiesterase 4 Inhibitors; D011422:Propionates; D011743:Pyrimidines; D011804:Quinolines; D014700:Verapamil; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C059141:verlukast