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

Abstract

1 Human cxl-acid glycoprotein (AAG), a plasma transport protein, has three main genetic variants, Fl, S and A. Native commercial AAG (a mixture of almost equal proportions of these three variants) has been separated by chromatography into variants which correspond to the proteins of the two genes which code for AAG in humans: the A variant and a mixture of the Fl and S variants (60% Fl and 40% S). Their binding properties towards imipramine, warfarin and mifepristone were studied by equilibrium dialysis.

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.…”

α1-Acid Glycoprotein Levels in Human Immunodeficiency Virus-Infected Subjects on Antiretroviral Regimens

“…1) may be partly due to the fact that AAG has been shown to be a mixture of two or three genetic variants encoded by at least two different genes (Herve et al, 1998). Moreover, drugs have different binding specificities for different AAG sites (Herve et al, 1993), and the wide interindividual variability in binding shown for indinavir (Anderson et al, 2000) may partly be explained by this. The sites where protease inhibitors bind are still unknown.…”

Selective Binding of Tamsulosin to Genetic Variants of Human .ALPHA.1-Acid Glycoprotein

“…The ratio of the Kd of tamsulosin for the A and F1/S variants was 11.4 and that of warfarin was 7. 3,5) indicating that the selectivity of these drugs for binding to the F1/S variant was comparable. The number of binding sites for the F1/S variant mixture and the A variant was almost one, whereas that for total AGP was 0.67, which was reasonably explained by assuming that 70% of the total AGP used in this study consisted of the F1/S variants, and this was confirmed by isoelectric focusing (data not shown).…”

“…[4][5][6] Accordingly, it has been suggested that human AGP has two main genetic variants for drug binding, and that each respective variant has different binding characteristics.…”

“…[4][5][6]11) Briefly, the IDA Sepharose gel loaded with copper(II) ions and equilibrated in buffer (20 mM sodium phosphate buffer, pH 7.0, containing 0.5 M NaCl) was packed into a glass column (1.5 cm I.D.ϫ 30.0 cm L). A commercial AGP (10 mg/ml) was applied to the column at a flow rate of 10 ml/h.…”