Stereoselective Disposition of Sulbenicillin in Humans

Abstract

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 theR-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 greaterfu 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 theR-epimer in plasma. It was revealed that stereoselective degradation in the body had significant influence on the disposition of SBPC epimers.

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney

“…Very few studies have compared the renal clearances of the enantiomers of secreted weak acids. Differences were observed in Cynomolgus monkeys between the isomers of a uricosuric agent, S-8666, which contains a carboxylic acid moiety (Nakano & Kawahara 1992), but there were no differences for sulbenicillin (Itoh et al 1998) or carbenicillin (Itoh et al 1993) in man. The authors are not aware of any studies comparing the renal clearance of the unbound enantiomers of NSAIDs.…”

Stereoselective binding and degradation of sulbenicillin in the presence of human serum albumin

“…It was found that the unbound fraction of S-SBPC was greater than that of R-SBPC, which was similar to that observed in human plasma. 15 Moreover, the extent of binding in 0.6 mM HSA solution was similar to that in human plasma for both isomers. These observations strongly suggest that albumin is the major binding protein in human plasma and that the stereoselectivity of the binding of SBPC in human plasma reflected that in the binding to HSA.…”

“…Degradation of R-SBPC observed in the present study is very similar to that observed in human plasma, i.e., R-SBPC degraded with a half-life of approximately 4 h both in 0.6 mM HSA and human plasma. 15 With a decrease of R-SBPC concentration, only a slight increase of S-SBPC concentration was observed (Fig. 5A), indicating that conversion of R-SBPC to S-SBPC is insignificant.…”

“…High-performance liquid chromatography was used to determine the concentrations of SBPC isomers. 15 The HPLC system consisted of a dual-piston pump (model LC-10AD), a UV detector (model SPD-10A), and an integrator (model C-R4A), all from Shimadzu Co. (Kyoto, Japan). The analytical column was Mightysil (RP-18, i.d.…”

“…We previously studied stereoselective disposition of SBPC diastereomers in humans. 15 It was revealed that stereoselective degradation of R-SBPC in plasma and interstitial fluids had significant influence on the stereoselective disposition of SBPC isomers. In the present study, stereoselective binding, isomer-isomer interactions, and stereoselective degradation of SBPC in the presence of HSA were studied.…”