Pharmacokinetic studies in animals of a new parenteral penem CP-65,207 and its oral prodrug ester.
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.
Gootz
T
T
Department of Biochemistry, University of Missouri, Columbia.
Girard
D
D
Schelkley
W
W
Tensfeldt
T
T
Foulds
G
G
Kellogg
M
M
Stam
J
J
Campbell
B
B
Jasys
J
J
Kelbaugh
P
P
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004150:Dipeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004285:Dogs; D004355:Drug Stability; D004952:Esters; D005260:Female; D006868:Hydrolysis; D015378:Imipenem / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007536:Isomerism; D007769:Lactams; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats
D000900:Anti-Bacterial Agents; D004952:Esters; D007769:Lactams; D011355:Prodrugs; D015378:Imipenem; C061362:CP 65207; D004150:Dipeptidases; C038937:dipeptidase