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Binding of bupivacaine to human serum proteins, isolated albumin and isolated alpha-1-acid glycoprotein. Differences between the two enantiomers are partly due to cooperativity

JX Mazoit, LS Cao and K Samii

Laboratoire d'Anesthesie, Universite de Paris-Sud, Faculte de Medecine du Kremlin-Bicetre, France.

Binding parameters of R(+)- and S(-)-bupivacaine were determined for human serum proteins, human alpha-1-acid glycoprotein (AAG) and human serum albumin (HSA), using ultrafiltration. Binding parameters were estimated according to the Scatchard model of the law of mass action using nonlinear regression. A sigmoid (cooperativity) term was added when needed. Both enantiomers exhibited a two site binding profile for human serum and for a solution containing AAG and HSA at physiological concentrations. At concentrations lower than 40 microM (concentrations encountered in clinical situations), the low capacity, high affinity apparent site was predominant and S(-)-bupivacaine exhibited a higher free fraction than R(+)-bupivacaine. At concentrations higher than 60 microM, the opposite situation was observed and the S(-) enantiomer showed much higher binding to AAG than the R(+) enantiomer. Two cooperativity phenomena occurred. Negative cooperativity was observed when AAG and HSA were combined in the same solution. S(-) and R(+) enantiomers exhibited different behavior toward purified AAG and HSA due in part to complex allosteric cooperativity (positive or negative depending on the ligand/protein ratio). In conclusion, we observed stereoselective binding of bupivacaine to AAG and HSA. Moreover, cooperativity occurred, and the behavior of the two enantiomers showed marked differences in this respect.

Volume 276, Issue 1, pp. 109-115, 01/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics.