Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans.
CP-65,207 is a new broad-spectrum penem antimicrobial agent that is a 1:1 mixture of two stereoisomers. Five minutes after a 10-min intravenous infusion of 1 g of CP-65,207 to volunteers, mean concentrations in serum were 33 micrograms of the R isomer per ml and 29 micrograms of the S isomer per ml. Following rapid distribution, half-lives of the isomers were 53 and 55 min, respectively. Concentrations in urine exceeded 800 micrograms of each isomer per ml. Recovery of the S isomer in urine (46%) was much greater than recovery of the R isomer (26%). The serum kinetics of the S isomer (volume of distribution, 319 ml/kg; total clearance, 315 ml/min; elimination rate constant, 0.80 h-1 were similar when it was given alone and when it was contained in CP-65,207, demonstrating that the presence of the R isomer has little effect on the serum kinetics of the S isomer. However, when the S isomer was given alone, the urinary recovery of intact S isomer (36%) was substantially lower than that when it was given with the R isomer as CP-65,207 (57%). Administration of the S isomer alone did not produce the unpleasant sulfurous odor in urine that was observed following administration of CP-65,207. Oral doses of a prodrug, which contained 1 g of CP-65,207, produced peak concentrations in serum of 1.6 micrograms of the R isomer per ml and 1.8 micrograms of the S isomer per ml. Approximately 36% of the S-isomer component was absorbed, and 20% of this isomer was recovered in urine. A 1-g oral dose of the prodrug of the single S isomer provides concentrations in serum above 1.0 microgram/ml (the MIC for 90% of over 1,000 hospital pathogens) for 3.5 h, suggesting that the drug given orally will prove to be efficacious against many infections.
Foulds
G
G
Drug Metabolism Department, Pfizer Inc., Groton, Connecticut 06340.
Knirsch
A K
AK
Lazar
J D
JD
Tensfelt
T G
TG
Gerber
N
N
D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007769:Lactams; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000493:pharmacokinetics; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D007769:Lactams; D011355:Prodrugs; C061362:CP 65207