Stereoselective irreversible binding of ketoprofen glucuronides to albumin. Characterization of the site and the mechanism. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue (Article De Synthèse) Drug Metabolism and Disposition Année : 1996

Stereoselective irreversible binding of ketoprofen glucuronides to albumin. Characterization of the site and the mechanism.

F Lapicque
  • Fonction : Auteur
S Fournel-Gigleux
  • Fonction : Auteur
J Magdalou
  • Fonction : Auteur
P Netter
  • Fonction : Auteur

Résumé

We have previously shown that the acyl glucuronide of racemic ketoprofen can irreversibly bind in vitro to plasma proteins (Dubois, N., et ai., Drug Metab. Dispos. 21, 617-623, 1993), but the mechanism of the reaction has not been characterized. In the present study, the reactivity toward albumin of the glucuronide of both ketoprofen enantiomers was investigated. The extent of binding increased with the concentration of both protein and glucuronide. However, the two diastereoisomers showed different reactivities toward human serum albumin (HSA): the maximum yield of adducts with the glucuronide of the S-enantiomer was twice that obtained with the glucuronide of its antipode. The maximum extent of irreversible binding was at 4 hr for the R-ketoprofen conjugate, but was later for the S-form. Chemical modifications of albumin indicated that the glucuronide of the S-isomer reacted only with lysine residues, whereas the R-form linked covalently mainly with tyrosine residues and secondarily with lysine residues. A competition study using specific binding probes and fatty acids showed that the conjugates of S- and R-ketoprofen reacted with amino acids located in sites I and II of HSA, respectively. Taken together, these findings suggest that the irreversible binding of ketoprofen to albumin depends on the stereochemistry of the aglycon: the R-enantiomer binds to site II of the protein probably by a nucleophilic attack by tyrosine and/or lysine residues, whereas adduct formation via the conjugate of the S-enantiomer could occur at site I of HSA by the Schiff base mechanism. This irreversible binding at sites I and II may affect the major function of albumin (i.e. the transport of drugs and endogenous compounds).
Fichier non déposé

Dates et versions

hal-04191069 , version 1 (30-08-2023)

Identifiants

  • HAL Id : hal-04191069 , version 1
  • PUBMED : 8894504

Citer

N Presle, F Lapicque, S Fournel-Gigleux, J Magdalou, P Netter. Stereoselective irreversible binding of ketoprofen glucuronides to albumin. Characterization of the site and the mechanism.. Drug Metabolism and Disposition, 1996, 24 (10), pp.1050-7. ⟨hal-04191069⟩

Collections

CNRS
3 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More