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.
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机译:研究了健康人类志愿者中舒美西林(SBPC)差向异构体的立体选择性处置,以阐明差向异构体之间的药代动力学行为差异。立体定向高效液相色谱法用于测定SBPC差向异构体。用超滤方法在体外测量血浆蛋白结合。结合是立体选择性的,R-受体的未结合部分(fu)约为S-受体的未结合部分(fu)的1.3倍。向人类志愿者静脉注射SBPC,并测量血浆中SBPC的浓度和尿液排泄率。对于两种差向异构体,未结合药物的肾清除率(CLR)(约400 ml / min)均大于肾小球滤过率(GFR)(约为109 ml / min),这表明两种差向异构体都分泌在肾小管上。 S受体的肾小管分泌似乎更大。当丙磺舒联合施用时,两种差向异构体的CLR值均显着降低,并且大约等于GFR值。 S-受体的CLR更大(R-SBPC和S-SBPC分别为37.5和49.8 ml / min),这仅是由于血浆中S-受体的功能更大。相反,由于血浆中R受体的立体选择性降解,R受体的总体清除率更高(R-SBPC和S-SBPC分别为67.8和56.3 ml / min)。揭示了体内的立体选择性降解对SBPC差向异构体的配置有重大影响。
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