Blood-brain barrier transport of CI-912: single-passage equilibration of erythrocyte-borne drug.

Brain capillary transit of CI-912 was studied in vivo after a single capillary transit by the intracarotid injection technique. Brain permeability of 14C-drug was measured relative to that of tritiated water, a highly diffusible reference substance. The brain uptake index of CI-912 was measured at concentrations ranging from 5 to 400 micrograms/ml in different regions of the rat brain. Brain uptake was not via a saturable, carrier-mediated mechanism, but was attributable to lipid-mediated transport. The octanol/saline partition coefficient determined in vitro was 3.9, and the blood-brain barrier permeability times surface area product was 0.26 ml min-1 g-1 (in vivo). In the rat brain, efflux of CI-912 after intracarotid injection was found to be minimal, suggesting that this drug is retained in brain tissues. This drug is weakly bound to plasma proteins (75-79% of the drug is freely dialyzable in 4% human serum albumin at 5 micrograms/ml), and protein binding does not affect brain uptake. In contrast, the drug is highly bound to erythrocytes. At concentrations that approximate the predicted optimum therapeutic range (6-40 micrograms/ml), it has been demonstrated that in addition to exchange of plasma-borne drug, erythrocyte-borne CI-912 is able to equilibrate across the blood-brain barrier in the course of a single transcapillary transit. Approximately one half of the drug gaining access to brain in a single transcapillary passage is erythrocyte-borne.