Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1-acid glycoprotein.
1. Human alpha 1-acid glycoprotein (AAG), a plasma transport protein, has three main genetic variants. F1. 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 F1 and S variants (60% F1 and 40% S). Their binding properties towards imipramine, warfarin and mifepristone were studied by equilibrium dialysis. 2. The F1S variant mixture strongly bound warfarin and mifepristone with an affinity of 1.89 and 2.06 x 10(6) l mol-1, respectively, but had a low affinity for imipramine. Conversely, the A variant strongly bound imipramine with an affinity of 0.98 x 10(6) l mol-1. The low degree of binding of warfarin and mifepristone to the A variant sample was explained by the presence of protein contaminants in this sample. These results indicate specific drug transport roles for each variant, with respect to its separate genetic origin. 3. Control binding experiments performed with (unfractionated) commercial AAG and with AAG isolated from individuals with either the F1/A or S/A phenotypes, agreed with these findings. The results for the binding of warfarin and mifepristone by the AAG samples were similar to those obtained with the F1S mixture: the mean high-affinity association constant of the AAG samples for each drug was of the same order as that of the F1S mixture: the decrease in the number of binding sites of the AAG samples, as compared with the F1S mixture, was explained by the smaller proportion of variants F1 and/or S in these samples. Conversely, results of the imipramine binding study with the AAG samples concurred with those for the binding of this basic drug by the A variant, with respect to the proportion of the A variant in these samples.
Herve
F
F
Laboratoire Hospitalo-Universitaire de Pharmacologie, Hôpital Intercommunal de Créteil. Faculté de Médecine de Paris, France.
Gomas
E
E
Duche
J C
JC
Tillement
J P
JP
D014644:Genetic Variation; D006801:Humans; D007099:Imipramine / Q000378:metabolism*; D066298:In Vitro Techniques; D015735:Mifepristone / Q000378:metabolism*; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014859:Warfarin / Q000378:metabolism*
D009961:Orosomucoid; D015735:Mifepristone; D014859:Warfarin; D007099:Imipramine