Interindividual differences in the binding of antidepressives to plasma proteins: the role of the variants of alpha1-acid glycoprotein

Abstract

Alpha 1-acid glycoprotein (AAG) is one of the plasma proteins that bind basic drugs, like amitriptyline (AT) and its metabolite nortriptyline (NT). Two types of genetic polymorphism have been described for AAG: polymorphic forms which, on electrophoresis of the native protein, give four patterns with 5, 6, 7 or 8 bands, and the variants which on by electrophoresis of the desialysed protein, give three patterns with 2 bands, FF, FS and SS. In 31 depressive patients, treated daily with 150 mg AT for 3 weeks, free and total plasma AT and NT were determined, as well as the AAG polymorphic forms and variants. There was only a weak negative correlation between the free fractions of AT and NT and total plasma AAG, but free AT and NT were strongly correlated with the S form (but not the F form) of AAG variants. The differences in binding might be the expression of a further genetic factor determining the steady-state plasma levels of tricyclic drugs.

Alpha 1‐acid glycoprotein concentration and molecular heterogeneity: relationship to oxprenolol binding in serum from healthy volunteers and patients with lung carcinoma or cirrhosis.

“…This is in keeping with the fact that the binding sites for the drug are probably located on the polypeptide chain of AAG rather than on the sugar part as suggested by Tinguely et al (1985).…”

“…It is the major serum tions of the different molecular forms and this high affinity binding protein for many basic sub-could contribute to the change in protein binding stances such as ,B-adrenoceptor blocking drugs, of basic drugs (Tinguely et al, 1985;Pedersen et antiarrhythmic and antidepressant drugs (Paxton, al., 1987). The purpose of the investigations 1983; Routledge, 1986).…”

Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1‐acid glycoprotein.

“…It is conceivable that the functional differences between the genetic variants of AAG could explain differences in drug-binding between individuals. This possibility is supported by the results of investigations suggesting a genetic contribution to the interindividual differences observed in the plasma binding of amitriptyline [30] and methadone [31]. Furthermore, AAG is an acute-phase reactant, the plasma concentration of which increases in association with various inflammatory states [24].…”

Characterization of genomic rearrangements of the α1-acid glycoprotein/orosomucoid gene in Ghanaians

“…The new polymorphisms of the AGP genes found in this study may play an important role in drug transport. The AGP, or ORM, in plasma is a main carrier protein of basic drugs and other ligands, for which the binding is different among polymorphisms (Tinguely et al 1985;Kremer et al 1988;Hervé et al 1993Hervé et al , 1996.…”