Pharmacokinetics and disposition of CS-023 (RO4908463), a novel parenteral carbapenem, in animals

Abstract

The distribution, metabolism, and excretion of CS-023 (RO4908463), a new carbapenem, were investigated in rats and monkeys after a single intravenous administration of [(14)C]CS-023. In addition, the drug's pharmacokinetics were examined in rats, dogs, and monkeys. Whole-body autoradioluminograms of rats indicated that the radioactivity is distributed throughout the body immediately after administration except for the central nervous system and testes. The highest radioactivity was found in the kidneys, which are responsible for the excretion of CS-023. R-131624 with an open beta-lactam ring, the pharmacologically inactive form, was detected in the plasma and urine as the major metabolite. In rat plasma, the R-131624 levels became higher than CS-023 levels at 30 min postdose and thereafter, while in monkey plasma, CS-023 accounted for most of the radioactivity, with low levels of R-131624. More than 80% of the radioactivity administered was recovered in the urine, and CS-023 and R-131624 accounted for 29.6% and 31.4%, respectively, of the dose in rats and 51.2% and 18.5%, respectively, of the dose in monkeys. The faster metabolism to R-131624 in rats than in monkeys was likely due to the metabolism by dehydropeptidase I in rat lungs. The plasma elimination half-life of CS-023 was 0.16 h in rats, 0.75 h in dogs, and 1.4 h in monkeys. There were no appreciable interspecies differences among the animals tested in either volume of distribution (172 to 259 ml/kg) or serum protein binding (5.0 to 15.6%). The total clearance in monkeys (1.62 ml/min/kg) was lower than that in rats (15.1 ml/min/kg) or dogs (4.19 ml/min/kg).

FIG. 1.

Chemical structures of [¹⁴C]CS-023 and R-131624. *, ¹⁴C-labeled position.

FIG. 2.

Whole-body autoradioluminograms after a single intravenous administration of [¹⁴C]CS-023 at a dose of 10 mg/kg to rats. GI, gastrointestinal.

FIG. 3.

Plasma concentration-time profiles after a single intravenous administration of [¹⁴C]CS-023 to rats (A) and monkeys (B) at a dose of 10 mg/kg. Each data point represents the mean ± the SD of three animals.

FIG. 4.

Typical TLC autoradioluminograms of radioactivity in plasma, urine, feces, and bile after a single intravenous administration of [¹⁴C]CS-023 to rats at a dose of 10 mg/kg.

FIG. 5.

Typical TLC autoradioluminograms of radioactivity in plasma, urine, and feces after a single intravenous administration of [¹⁴C]CS-023 to monkeys at a dose of 10 mg/kg.

FIG. 6.

Time courses of cumulative excretion ratios of radioactivity after a single intravenous administration of [¹⁴C]CS-023 to rats (A) and monkeys (B) at a dose of 10 mg/kg. Each data point represents the mean ± the SD of four rats or three monkeys, respectively.

FIG. 7.

Plasma concentration-time profiles of CS-023 after a single intravenous administration of CS-023 to rats (A), dogs (B), and monkeys (C). The limit of quantitation was 1 μg/ml for rat and dog plasma and 2 μg/ml for monkey plasma. Each data point represents the mean ± the SD of three animals.