Role of biantennary glycans and genetic variants of human alpha(1)-acid glycoprotein in enantioselective binding of basic drugs as studied by high performance frontal analysis/capillary electrophoresis
Y. Kuroda et al., Role of biantennary glycans and genetic variants of human alpha(1)-acid glycoprotein in enantioselective binding of basic drugs as studied by high performance frontal analysis/capillary electrophoresis, PHARM RES, 18(3), 2001, pp. 389-393
Purpose. To establish a clear understanding of the role of biantennary bran
ching glycans and genetic variants of alpha (1)-acid glycoprotein (AGP) in
enantioselective bindings of basic drug.
Methods. Human native AGP was separated using concanavalin A affinity chrom
atography into two subfractions, the unretained fraction (UR-AGP, defect of
biantennary glycan) and the retained fraction (R-AGP, possessing biantenna
ry glycan(s)). Imminodiacetate-copper (II) affinity chromatography was used
to separate human native AGP into A variant and a mixture of Fl and S vari
ants (F1*S variants). The mixed solutions of the (R)- or (S)-isomer of the
model drugs (15 muM disopyramide (DP) or 30 muM verapamil (VER)) and 40 muM
of respective AGP species were subjected to high-performance frontal analy
sis/capillary electrophoresis (HPFA/CE) to determine the unbound drug conce
Results. The unbound concentrations (Cu) of DP in UR-AGP solutions were low
er than those in R-AGP solutions, whereas there was no significant differen
ce in the enantiomeric ratios (Cu(R)/Cu(S)) of DP between UR- and R-AGP sol
utions. In case of genetic variant, the Cu(R)/Cu(S) values of DP in F1*S an
d A solutions were 1.07 and 2.37, respectively. On the other hand, the enan
tiomeric ratio of VER in F1*S and A variant solutions were 0.900 and 0.871.
Conclusions. The biantennary glycan structures are related to binding affin
ity of DP to AGP, but not responsible for the enantioselectivity. Genetic v
ariants give significant effect on the enantioselectivity in DP binding, bu
t not in VER binding.