Enantioselective inhibition of the binding of rac-profens to human serum albumin induced by lithocholate.
The reversible binding of lithocholate to human serum albumin determines a decrease of the binding of rac-ketoprofen. The process was followed by displacement chromatography using increasing concentrations of the competitor, i.e., lithocholate, in the mobile phase. The inhibition of rac-ketoprofen binding resulting was enantioselective and greater displacement was observed for the (S) enantiomer. The displacement process resulting was competitive in nature, the two enantiomers of ketoprofen binding to the same binding site as the modifier. The investigation was extended to other nonsteroidal antiinflammatory drugs. The enantioselective binding inhibition was larger in the case of rac-naproxen and rac-suprofen with respect to the phenomenon observed in the case of rac-ketoprofen. The difference in circular dichroism spectroscopy was also used to characterize the binding of lithocholate to human serum albumin. This bile acid was proven to bind to site II on human serum albumin. The results, as obtained by displacement chromatography and difference circular dichroism spectroscopy, strongly support the hypothesized role of bile acids in inducing the enantioselective inhibition of ketoprofen binding to human serum albumin in patients suffering from liver diseases.
Bertucci
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Dipartimento di Scienze Farmaceutiche, Università di Bologna, 40126 Bologna, Italy. bertucci@alma.unibo.it
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D002845:Chromatography; D002942:Circular Dichroism; D004347:Drug Interactions; D005279:Fenoprofen / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007660:Ketoprofen / Q000037:antagonists & inhibitors / Q000378:metabolism; D008095:Lithocholic Acid / Q000378:metabolism / Q000494:pharmacology*; D009288:Naproxen / Q000037:antagonists & inhibitors / Q000378:metabolism; D010666:Phenylpropionates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013496:Suprofen / Q000037:antagonists & inhibitors / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; D012709:Serum Albumin; D009288:Naproxen; D008095:Lithocholic Acid; D007660:Ketoprofen; D013496:Suprofen; D005279:Fenoprofen