Pharmacokinetics of meropenem, a new carbapenem antibiotic, parenterally administrated to laboratory animals

The pharmacokinetics of meropenem (MEPM), a new carbapenem antibiotic, were studied in mice, rats, guinea pigs, rabbits, dogs and monkeys. The peak plasma levels of MEPM intravenously administered at a dose of 20 mg/kg were 64.0 µg/ml in mice, 99.8 µg/ml in rats, 82.2 µg/ml in guinea pigs, 99.2 µg/ml in rabbits, 133 µg/ml in dogs and 93.4 µg/ml in monkeys. The plasma half-lives of MEPM were 4.5 min in mice, 3.0 min in rats, 12.9 min in guinea pigs, 20.8 min in rabbits, 40.8 min in dogs and 30.9 min in monkeys; the plasma half-lives in mice and rats were about one-half or one-third of those of imipenem (IPM), although MEPM and IPM showed almost the same half-lives in guinea pigs. The urinary excretion rates of MEPM were 34.1% of the dose in mice, 25.0% in rats, 42.5% in guinea pigs, 34.6% in rabbits, 49.1% in dogs and 25.7% in monkeys. A dose-proportionality study was conducted with intravenous doses of 5 to 50 mg/kg in mice and guinea pigs. The AUCs were linearly proportional to doses. These findings suggest that tissue distribution and the excretion pathway were independent of administration dose. The tissue levels of MEPM given to mice, rats and guinea pigs by the intravenous route at a dose of 20 mg/kg were the highest in plasma, followed in descending order by liver, kidney, heart, lung and spleen in mice, and kidney, liver, heart and spleen in rats. In guinea pigs, the order was plasma, lung, heart, kidney, spleen and liver. The half-lives of MEPM in 10% lung homogenate from various experimental animals were 84 min in mice, 42 min in rats, 1210 min in guinea pigs, 247 min in rabbits, 1000 min in dogs and 209 min in monkeys. The stability of MEPM against renal dehydropeptidase-I (DHP-I) varied greatly with the animal source of the enzyme. MEPM was more easily hydrolyzed than IPM by DHP-I from mice, rabbits and monkeys, but was more stable than IPM in guinea pigs, dogs and human DHP-I. The serum protein bindings of MEPM were 33.8% in mice, 14.1% in rats, 15.8% in guinea pigs, 21.2% in rabbits, 7.5% in dogs, 7.9% in monkeys and 13% in humans.