Disposition of CP-671,305, a selective phosphodiesterase 4 inhibitor in preclinical species

1. The disposition of (+)- 2-[4-({[2-(benzo[1,3] dioxol-5-yloxy)-pyridine-3-carbonyl]amino}- methyl)-3-fluoro-phenoxy]-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 +/- 0.87 ml 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 mg kg(-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 muM). 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) pro. le 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.