Foulds G, Knirsch A K, Lazar J D, Tensfelt T G, Gerber N
Drug Metabolism Department, Pfizer Inc., Groton, Connecticut 06340.
Antimicrob Agents Chemother. 1991 Apr;35(4):665-71. doi: 10.1128/AAC.35.4.665.
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.
CP - 65,207是一种新型广谱青霉烯类抗菌剂，它是两种立体异构体的1:1混合物。在向志愿者静脉输注1克CP - 65,207 10分钟后，血清中R异构体的平均浓度为每毫升33微克，S异构体的平均浓度为每毫升29微克。快速分布后，异构体的半衰期分别为53分钟和55分钟。尿液中每种异构体的浓度超过每毫升800微克。S异构体在尿液中的回收率（46%）远高于R异构体（26%）。S异构体单独给药时和包含在CP - 65,207中时的血清动力学（分布容积，319毫升/千克；总清除率，315毫升/分钟；消除速率常数，0.80小时-1）相似，这表明R异构体的存在对S异构体的血清动力学影响很小。然而，单独给予S异构体时，完整S异构体的尿液回收率（36%）明显低于与R异构体作为CP - 65,207一起给药时（57%）。单独给予S异构体不会产生CP - 65,207给药后在尿液中观察到的难闻的硫磺气味。口服含1克CP - 65,207的前药，血清中R异构体的峰值浓度为每毫升1.6微克，S异构体的峰值浓度为每毫升1.8微克。约36%的S异构体成分被吸收，其中20%的该异构体在尿液中回收。口服1克单一S异构体的前药，血清浓度在3.5小时内高于1.0微克/毫升（1000多种医院病原体中90%的最低抑菌浓度），这表明口服该药物对许多感染将证明是有效的。
