THE EFFECT OF 3 H-2-RECEPTOR ANTAGONISTS ON THE DISPOSITION OF MIDAZOLAM IN THE RAT IN-SITU PERFUSED LIVER MODEL

The rat in-situ perfused liver model was used to investigate the effec t of three H-2-receptor antagonists on the pharmacokinetic disposition of the short-acting benzodiazepine, midazolam. Perfusion experiments, using standard techniques, were carried out on four groups (one contr ol and three H-2-receptor antagonist-treated groups) of male Sprague-D awley rats (300-350g). All animals received midazolam 1 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg) or famoti dine (0.4 mg). Perfusate and bile samples were collected and assayed f or midazolam using gas chromatography. The perfusate data indicated th at midazolam disposition was impaired at 10, 50 and 60 min of the expe rimental period following the addition of cimetidine, whereas ranitidi ne and famotidine produced an effect at 10 min only; midazolam levels in bile were not affected by the presence of an H-2-receptor antagonis t. It was concluded that the limited inhibitory effect of cimetidine m ay be attributed to its lack of specificity for CYP3A, the isoenzyme r esponsible for the metabolism of midazolam.