Pharmacokinetic studies of CP-74,667, a new quinolone, in laboratory animals

Abstract

The pharmacokinetics of CP-74,667 (7-(8'-methyl-3',8'-diazabicyclo[3.2.1]oct-3'-yl)-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) were studied following oral or parenteral administration in mice, rats, rabbits, dogs, and cynomolgus monkeys. The mean peak levels of CP-74,667 in serum following a single oral dose of 20 mg/kg of body weight were similar in all species, with a range of 3.7 micrograms/ml in mice to 5.6 micrograms/ml in dogs. In contrast, elimination half-lives were species dependent, with mean values of 2.1, 1.8, 4.5, 7.8, and 13.1 h in mice, rats, rabbits, dogs, and monkeys, respectively. The oral bioavailability of CP-74,667 was 100% in dogs and monkeys, as determined by intravenous-oral crossover experiments. The maximum concentration of drug in serum and area under the concentration-time curve (AUC) of CP-74,667 in dogs were proportional to dose over the range of 5 to 40 mg/kg. Accumulation of drug in serum was observed following the administration of four once-a-day doses of 7.1 mg/kg in monkeys (mimicking a 500-mg human dose), with significant increases in half-life, maximum and minimum concentrations of drug in serum, and AUC. The good tissue penetration of CP-74,667 suggested by a volume of distribution in excess of 2 liters/kg in dogs and monkeys was confirmed by tissue distribution studies with the same species, which demonstrated tissue concentrations (except for those in brain tissue) greater than 1.45 times higher than corresponding levels in serum. The mean urinary recoveries of unchanged drug were 17.7% in rats, 7.8% in monkeys, and 4.9% in dogs. Metabolism studies in dogs, following intravenous dosing, indicated that renal excretion of CP-74,667-related materials accounted for 41.6% of the administered dose, while biliary recoveries accounted for 6.8%. The CP-74,667 N-oxide metabolite was the primary drug-related material eliminated via renal excretion (37.2% of dose). The pharmacokinetics of CP-74,667 describe a quinolone with complete oral absorption, linear pharmacokinetics, a long elimination half-life, and wide distribution into tissues.