Pharmacokinetic studies in animals of a new parenteral penem CP-65,207 and its oral prodrug ester

Abstract

The pharmacokinetics of penem CP-65,207 diastereomeric mixture were studied following parenteral administration in mice, rats, beagle dogs and cynomolgus monkeys. As is characteristic for most penems, the serum elimination T1/2 of CP-65,207 in rodents was only 13 minutes for mice and 18 minutes for rats. A linear relationship was observed between dose and Cmax following subcutaneous injection of drug in mice. The T1/2 in the beagle dog and monkey following intravenous injection was approximately 23 minutes. CP-65,207 demonstrated binding to human serum proteins of only 10%. In vitro studies using purified porcine renal dehydropeptidase-I (RDHP) indicated that the pure S-isomer of CP-65,207 was 7-fold more stable to inactivation than imipenem. Urinary recovery of CP-65,207 in the dog was 42% compared to 1% for imipenem without RDHP inhibitor. Unlike results obtained with imipenem, coadministration of probenecid with CP-65,207 in the dog doubled the elimination T1/2 and AUC of the penem demonstrating its relative stability in vivo in the absence of a RDHP inhibitor. The pivaloyloxymethyl esters of each pure isomer of CP-65,207 showed significantly different degrees of oral absorption in rats.