Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug.

Brain extraction of two calcium channel antagonists, isradipine (PN 200-110) and darodipine (PY 108-068) was investigated using the carotid injection technique in rats. An inhibitor effect of binding to plasma proteins on the brain extraction was also investigated. Equilibrium dialysis at 37 degrees C showed that both drugs were highly bound to human serum proteins, including albumin, alpha-1 acid glycoprotein and lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. The brain extraction of the drugs in the presence of either albumin or alpha-1 acid glycoprotein was inversely related to the protein concentrations in the presence of either albumin or alpha-1 acid glycoprotein, but it was higher than expected from the in vitro measurement of the dialyzable fraction. Despite a significant degree of binding to lipoproteins, no significant reduction in the brain extraction of the drugs was observed, regardless of the class or the concentration of lipoproteins. These data indicate that the amount of circulating darodipine or isradipine available for entry in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein bound.