Restrictive transport of a lipid-soluble peptide (cyclosporin) through the blood-brain barrier.

The blood-brain barrier (BBB) transport of a highly lipid-soluble peptide, [3H]cyclosporin, was studied in ketamine-anesthetized rats using the carotid artery injection technique. For comparison, peptide transport into rat liver was also assessed with the portal vein injection technique. Despite the high lipid solubility of this peptide (1-octanol/Ringer's partition coefficient = 991 +/- 55), the extraction by rat brain was only 2.9 +/- 0.5% in the presence of 80% human serum, and this value approximated the extraction for a poorly diffusible substance such as [3H]inulin, 2.0 +/- 0.1%. In contrast, the hepatic extraction of [3H]cyclosporin was high, 84 +/- 2%, in the presence of 80% human serum. The BBB transport of cyclosporin is markedly restricted owing to the combined effects of binding by serum proteins and a paradoxically low permeability of the BBB to the peptide.