Comparison of propranolol-binding plasma proteins in sheep with those in humans, dogs and rats.
Alpha 1-acid glycoprotein (AGP), a plasma protein responsible for the binding of a variety of basic lipophilic drugs including propranolol, is different from other plasma proteins in being nonprecipitable after treatment with 1.2M perchloric acid (PCA). To assess the contribution of AGP to drug disposition in sheep and three other species (rats, dogs, and humans), the binding of [3H]propranolol was measured before and after PCA precipitation. PCA precipitation reduced propranolol binding 14-fold in sheep, compared to 2- to 3-fold in the other species. This implied either that sheep AGP binds less propranolol than other species, or that the AGP in sheep is more precipitable. It was not due to inherently poor propranolol binding, as whole sheep plasma bound a higher fraction than the other species. When samples of PCA-precipitated sheep plasma were analyzed using polyacrylamide gel electrophoresis, the concentration of AGP was 10-20% that of the other species. Phenobarbital induction was used as a tool to examine the changes in the plasma protein profile. Phenobarbital induced propranolol binding and AGP along with two other proteins in sheep. One of these proteins migrated similarly to AGP deglycosylated by peptide-N-glycosidase F. It is postulated that the greater precipitability of propranolol binding in sheep is due to a less glycosylated form of AGP which is not important in other species.
Hill
M D
MD
Department of Pharmacology, George Washington University Medical Center, Washington, DC 20037.
Briscoe
P R
PR
Abramson
F P
FP
D000818:Animals; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006031:Glycosylation; D006801:Humans; D008297:Male; D009961:Orosomucoid / Q000378:metabolism*; D010472:Perchlorates; D010634:Phenobarbital / Q000494:pharmacology; D011247:Pregnancy; D011433:Propranolol / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism*; D012756:Sheep / Q000097:blood*
D009961:Orosomucoid; D010472:Perchlorates; D011955:Receptors, Drug; D011433:Propranolol; D010634:Phenobarbital