Influence of blood components on the tissue uptake indices of cyclosporin in rats.

The effect of blood components on the transfer of cyclosporin into brain, salivary gland, liver and kidney was measured in rats by an an vivo double isotope, tissue-sampling single injection technique. The brain-, salivary gland- and liver extraction of [3H] cyclosporine relative to [14C]butanol were studied with an intracarotid and a portal vein injection technique; the kidney extraction of [3H]cyclosporin relative to p[14C]aminohippuric acid was measured after a rapid injection in the aorta. The injection vehicles were a Ringer's solution [Ringer-4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid], rat plasma, human plasma, human red blood cells (RBC) suspension and human blood. The brain extraction (1-4%), the salivary extraction (25-74%) and the kidney extraction (8-47%) varied markedly depending on which blood components were added to the injection solution. The effect of RBC binding on tissue extraction was by far more pronounced than that of plasma protein binding. The binding of cyclosporin to RBC retards particularly the uptake of this drug by kidney. Moreover the kidney penetration of cyclosporin was confirmed by thaw-mount autoradiography after injection of the labeled drug in the aorta; the micrographs showed that the renal clearance of cyclosporin was restricted largely to the glomerular route. In contrast the hepatic extraction of [3H]cyclosporin was high (48-84%) and generally nonlimited by its binding to blood components; this could explain the high concentrations of drug observed in this tissue. In summary, cyclosporin binding to RBC and plasma proteins reduces drug uptake by brain, kidney and salivary gland, but causes little inhibition of hepatic uptake of cyclosporin.