Itoh T, Watanabe N, Ishida M, Tsuda Y, Koyano S, Tsunoi T, Shimada H, Yamada H
Department of Pharmacokinetics and Biopharmaceutics, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Antimicrob Agents Chemother. 1998 Feb;42(2):325-31. doi: 10.1128/AAC.42.2.325.
Stereoselective disposition of sulbenicillin (SBPC) epimers in healthy human volunteers was studied in order to clarify the differences in pharmacokinetic behavior between the epimers. Stereospecific high-performance liquid chromatography was used for the determination of SBPC epimers. Plasma protein binding was measured in vitro with an ultrafiltration method. The binding was stereoselective, with the unbound fraction (fu) of the R-epimer being approximately 1.3-fold greater than that of the S-epimer. SBPC was administered intravenously to human volunteers, and concentrations of SBPC in plasma and urinary excretion rates were measured. Renal clearance (CLR) for the unbound drug (approximately 400 ml/min) was greater than the glomerular filtration rate (GFR) (approximately 109 ml/min) for both epimers, suggesting that both epimers are secreted at the renal tubules. Renal tubular secretion appeared to be greater for the S-epimer. When probenecid was coadministered, the CLR values of both epimers were significantly reduced and were approximately equal to the GFR values. CLR was greater for the S-epimer (37.5 and 49.8 ml/min for R-SBPC and S-SBPC, respectively), which was simply due to the greater fu of the S-epimer in plasma. In contrast, total body clearance was greater for the R-epimer (67.8 and 56.3 ml/min for R-SBPC and S-SBPC, respectively) because of the stereoselective degradation of the R-epimer in plasma. It was revealed that stereoselective degradation in the body had significant influence on the disposition of SBPC epimers.
为了阐明舒苄西林（SBPC）差向异构体在药代动力学行为上的差异，对其在健康人体志愿者中的立体选择性分布进行了研究。采用立体特异性高效液相色谱法测定SBPC差向异构体。用超滤法体外测定血浆蛋白结合率。结合具有立体选择性，R-差向异构体的未结合分数（fu）约为S-差向异构体的1.3倍。将SBPC静脉注射给人体志愿者，并测定血浆中SBPC的浓度和尿排泄率。两种差向异构体的游离药物肾清除率（CLR）（约400 ml/min）均高于肾小球滤过率（GFR）（约109 ml/min），表明两种差向异构体均在肾小管分泌。S-差向异构体的肾小管分泌似乎更多。当同时给予丙磺舒时，两种差向异构体的CLR值均显著降低，且约等于GFR值。S-差向异构体的CLR更高（R-SBPC和S-SBPC分别为37.5和49.8 ml/min），这仅仅是因为S-差向异构体在血浆中的fu更高。相比之下，R-差向异构体的总体清除率更高（R-SBPC和S-SBPC分别为67.8和56.3 ml/min），这是由于R-差向异构体在血浆中的立体选择性降解。结果表明，体内的立体选择性降解对SBPC差向异构体的分布有显著影响。
