The pharmacokinetics of penemCP-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 Cmaxfollowing 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 ofCP-65,207 in the dog was 42%compared to 1 % for imipenem without RDHPinhibitor. Unlike results obtained with imipenem, coadministration of probenecid with CP-65,207 in the dog doubled the elimination T1/2 and AUCof the penem demonstrating its relative stability in vivo in the absence of a RDHPinhibitor. The pivaloyloxymethyl esters of each pure isomer of CP-65,207 showed significantly different degrees of oral absorption in rats.Carbapenem and penem antimicrobials are /Mactams that have demonstrated broad spectrum and high potency in vitro2~9). Aside from their antibacterial potency, some penems show oral absorption in vivo, and all are susceptible to hydrolysis by renal dehydropeptidase-I (RDHP)found in the brush border of the kidney in animals and man10'11*. Imipenem is the first carbapenem used clinically and it is coadministered with a RDHPinhibitor to block its high degree of renal metabolism12~14>. Several reports have studied the pharmacokinetics of experimental penemand carbapenem antimicrobials in an attempt to predict the performance of these compounds in humans12>15'16). Hajdu et al.17) determined that in rodents, extensive extrarenal metabolism of some analogs occurred by dehydropeptidases and that susceptibility to these enzymes significantly affected pharmacokinetic parameters in this model. In another report15), interspecies pharmacokinetic scaling in animals of penem SCH-34343 was useful in predicting the plasma elimination T1/2 of this compoundin man. Studies in several animal species were also helpful in elucidating the renal metabolism of imipenem12). CP-65,207 (Fig. 1) is a new broad spectrum penem antimicrobial for parenteral administration that is composed of an equal mixture by weight of S and i?-stereoisomers18). The current study evaluates the pharmacokinetics of this compoundin mice, rats, dogs, and cynomolgus monkeys. The oral absorption of the pivaloyloxymethyl (POM)ester of CP-65,207 is also studied in rats and monkeys. Finally, the effect of RDHPon the metabolism of CP-65,207 is compared relative to that of imipenem.
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