Abstract

The brain uptake of a number of benzodiazepines with different lipophilic and protein binding characteristics was investigated in male Sprague-Dawley rats using the rapid intracarotid artery injection technique. When the compounds were administered as a solution in Ringer's buffer, pH 7.4, the uptake was in the order of [14C]diazepam greater than [14C]L-663,581 (anxiolytic agent) greater than [3H]L-364,718 (morphine analgesia potentiator) greater than [14C]L-365,260 (anxiolytic agent) and their extraction ratio values were 71.0 +/- 6.8, 65.0 +/- 12.0, 42.0 +/- 5.0 and 6.0 +/- 2.0%, respectively. The respective permeability-surface product values were 0.755 +/- 0.152, 0.647 +/- 0.180, 0.329 +/- 0.05 and 0.035 +/- 0.011 ml/min/g. The rank order of brain extraction did not correlate well with the drugs' lipophilicity determined by octanol-buffer partition coefficient. For example, L-365,260 had the highest octanol/buffer partition coefficient, but the lowest brain extraction. Plasma protein binding significantly decreased the uptake by the brain but to a lesser extent than that predicted from the unbound drug fraction in vitro, suggesting that drug binding to plasma protein did not limit the transport of drug through the blood-brain barrier. For one compound, L-364,718, the extraction ratio and permeability-surface product values were increased markedly in CC1(4)-induced hepatic injury. Other disease states, uranyl nitrate-induced renal failure and streptozotocin-induced diabetes, had no apparent effect on the uptake of the compounds tested. The effect of disease state on the brain uptake of drug appeared to be dependent on the type of disease and the type of drug studied.