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Pharm Res. 2006 May;23(5):1038-42. Epub 2006 May 2.

Biantennary glycans as well as genetic variants of alpha1-acid glycoprotein control the enantioselectivity and binding affinity of oxybutynin.

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1
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

Abstract

PURPOSE:

The purpose of this study was to investigate the role of biantennary branching glycans of alpha1-acid glycoprotein (AGP) and its genetic variants in the enantioselective binding of oxybutynin (OXY).

METHOD:

Human native AGP was separated using imminodiacetate-copper (II) affinity chromatography into two fractions, the A variant and a mixture of the F1 and S variants (F1-S). These fractionated AGPs were further separated by concanavalin A affinity chromatography into two fractions, with and without biantenarry glycans. An on-line high-performance liquid chromatography (HPLC) system consisting of a high-performance frontal analysis column, an extraction column, and an analytical HPLC column was developed to determine the binding affinities of OXY enantiomers for respective AGP species.

RESULTS:

The total binding affinity as well as the enantiomeric selectivity of OXY in the F1-S mixed variant was significantly higher than that for the A variant, indicating that the chiral recognition ability of native AGP for the OXY enantiomers highly depends on the F1-S mixed variant. Furthermore, not only the genetic variants but also bianntenary glycans of AGP affect the binding affinity of OXY and are also responsible for the enantioselectivity.

CONCLUSIONS:

Both genetic variants and glycan structures significantly contribute to the enantioselectivity and the binding affinity of OXY.

PMID:
16715395
DOI:
10.1007/s11095-006-9777-8
[Indexed for MEDLINE]
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