title: Disposition of CP-671, 305, a selective phosphodiesterase 4 inhibitor in preclinical species.
abstract: 1. The disposition of (+)-2-[4-({[2-(benzo[1,3] dioxol-5-yloxy)-pyridine-3-carbonyl]-amino)-methyl)-3-fluoro-phenoxyl-propionic acid (CP-671,305), a potent and selective inhibitor of phosphodiesterase 4 (subtype D), was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 2. CP-671,305 demonstrates generally favourable pharmacokinetic properties in all species examined. Systemic plasma clearance after intravenous administration was low in Sprague-Dawley rats (9.60+/-1.16 ml min(-1) kg(-1)), beagle dogs (2.90+/-0.81 ml min(-1) kg(-1)) and cynomolgus monkeys (2.94+/-0.87ml min(-1) kg(-1)) resulting in plasma half-lives > 5 h. Moderate to high bioavailability in rats (43-80%), dogs (45%) and monkeys (26%) was observed after oral dosing. In rats, oral pharmacokinetics were dose dependent over the dose range studied (10 and 25 mgkg(-1)). 3. CP-671,305 was > 97% bound to plasma proteins in rat, dog, monkey and human. 4. The principal route of clearance of CP-671,305 in rats and dogs was by renal and biliary excretion of unchanged drug. This finding was consistent with CP-671,305 resistance towards metabolism in hepatocytes and NADPH-supplemented liver microsomes from preclinical species and human. 5. CP-671,305 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50's > 50 microM). Likewise, no time-dependent inactivation of the five major cytochrome P450 enzymes was discernible with CP-671,305. 6. Overall, the results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of CP-671,305 is relatively consistent across preclinical species and predict potentially favourable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans.
authors.affiliation: Department of Pharmacokinetics, Pfizer Global Research and Development, Groton, CT 06340, USA. amit_kalgutkar@groton.pfizer.com
authors.forename: A S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: E
authors.initials: E
authors.lastname: Choo
authors.forename: T J
authors.initials: TJ
authors.lastname: Taylor
authors.forename: A
authors.initials: A
authors.lastname: Marfat
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D011422:Propionates / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011422:Propionates; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4