title: Interspecies differences in the effect of pH on gallopamil protein binding to albumin and alpha 1-acid glycoprotein.
abstract: There is little information about the factors which influence drug protein binding between species. We have therefore investigated the role of pH on the binding of gallopamil, a calcium channel antagonist known to exhibit pH-sensitive binding, among four species, human, baboon, bovine, and canine. We used pure protein solutions of alpha 1 acid glycoprotein (AAG) (60 mg.l-1), albumin (45 gm.l-1), and their combination and three values of pH, 7.0, 7.4, and 8.0. Gallopamil protein binding was determined over a concentration range of 2.0 x 10(-7) mol.l-1 to 2.1 x 10(-3) mol.l-1 using equilibrium dialysis. Gallopamil binding in all solutions was best described using a two binding site model in the combination solution and a one binding site model in the pure solutions. pH did not affect the number of identical binding sites. However, the influence of pH on gallopamil binding was species specific. Increasing the pH from 7.0 to 8.0 influenced binding affinity differently between species. There were directionally similar changes in unbound fraction at a gallopamil concentration of 2 x 10(-7) mol.l-1 as pH increased, although there were species differences in the degree of change. In protein solutions containing both AAG and albumin a reduction in pH from 7.4 to 7.0 resulted in species-specific increases in the unbound fraction. Increasing the pH from 7.4 to 8.0 again resulted in species-specific reductions in the unbound fraction of gallopamil. Similar changes were seen when pure AAG or albumin solutions were used, indicating species variance in both gallopamil protein binding and the effect of pH on binding.
authors.affiliation: Cardiovascular Research Laboratory, College of Pharmacy, Detroit, Michigan 48202.
authors.forename: D R
authors.initials: DR
authors.lastname: Rutledge
authors.forename: M T
authors.initials: MT
authors.lastname: Chong
authors.forename: M V
authors.initials: MV
authors.lastname: Nelson
mesh_terms: D000136:Acid-Base Equilibrium; D000818:Animals; D002417:Cattle; D004285:Dogs; D005711:Gallopamil / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009961:Orosomucoid / Q000378:metabolism*; D010215:Papio; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D009961:Orosomucoid; D012709:Serum Albumin; D005711:Gallopamil