PHARMACOKINETICS OF A NOVEL QUINOLONE, AT-4140, IN ANIMALS

The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-p iperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 μg/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h., respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after β-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9, 8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18.9%, respectively, after β-glucuronidase treatment. The pharmacokinetics of AT-4140 may be characterized by its good tissue penetration and its long half-life in plasma and tissues.