Inhibition of blood-brain barrier permeability to DL-propranolol by serum from acute renal failure rats.

The effect of uranyl nitrate-induced acute renal failure on the brain uptake of DL-propranolol was investigated in rats with a series of tissue-sampling single-carotid injection techniques. When the buffer solution was used as an injection solution, the brain uptake index (BUI), the extraction ratio (ET), and the blood-brain barrier (BBB) permeability-surface area product (PSapp) and PSu (corrected PSapp for the unbound fraction) in uremic rats were significantly lower than those in control rats. These parameters for DL-propranolol were decreased significantly in both control and uremic rats receiving injection of the uremic serum. The PSu values in both of the control and uremic rats injected with either control or uremic rat serum were significantly higher than those in rats injected with the buffer solution, suggesting the presence of a protein-mediated transport mechanism; that is, the conventional assumption that the fraction of the drug which is available for the uptake in vivo is equal to the unbound fraction as measured in vitro may not hold. In contrast, the brain extraction of D-[14C]glucose, [3H]inulin and [3H]water, which show no binding to serum protein, was not affected by the coinjection of either control or uremic rat serum. On the other hand, using either the ultrafiltrate from serum (control and uremic) or supernatant fraction from heat-treated serum (control and uremic) as the injection solution, no significant difference in the PSu value for DL-propranolol was observed between control and uremic serum. These results suggest that (1) the decrease in the PSu value for DL-propranolol in uremic rats may be attributed mainly to the presence of an endogenous inhibitory substance(s) for the brain uptake or to the decrease in the exchangeable fraction in vivo in the uremic serum; (2) the decrease in the PSu value for DL-propranolol may also be partly attributed to the change in the BBB permeability and/or surface area; (3) the inhibitor for the brain uptake may be characterized as a temperature-sensitive and nonfiltrable substance(s) at physiological pH; and (4) the ability of protein-mediated transport for DL-propranolol into brain was decreased in uremic rats.