The genetic variant A of human alpha 1-acid glycoprotein limits the blood to brain transfer of drugs it binds.

The objective of this work was to check the effects of alpha-1 acid glycoprotein (AAG) and of its components, A and F1/S genetic variants, on the brain transfer of drugs they bind in plasma. The relevant extractions of six basic drugs, highly bound to AAG, were measured. We chose three drugs selectively bound to the A variant, disopyramide, imipramine and methadone, one drug mainly bound to the mixture F1/S, mifepristone, and two drugs which were simultaneously bound to the variant A and the mixture F1/S, propranolol and chlorpromazine. Their brain extraction were investigated in rats using the carotid injection technique and the capillary depletion method. Injected drugs were dissolved either in buffer, either in native AAG containing the three variants (A, F1 and S), either in variant A or in variant F1/S solutions. Brain extractions of disopyramide, imipramine and methadone were significantly reduced by native AAG and by variant A. Drug's plasma retention was related to their preferential and almost exclusive binding to A variant, both of them exhibiting the same decrease in brain transfer as compared to a buffered solution. At the opposite, there were no significative differences between the extraction either in buffer, either in AAG or in F1/S solutions, of drugs both bound to A variant and F1/S mixture (chlorpromazine and propranolol) or to the F1/S mixture (mifepristone). In serum, the retentional effect of the A variant on the extraction of disopyramide and imipramine was counteracted by the presence of albumin and lipoproteins, which simultaneously bind these two drugs at a high extent and act as permissive binders. We conclude that AAG binding decreases brain drug transfer when the A variant is mainly and almost exclusively involved in the binding. On the contrary, the entire fraction of the tested drugs when bound exclusively or partly to the mixture F1/S is available for transfer into the brain.