The in situ perfused rat liver model was used to investigate the effect of three H2 receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300-350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for CyA, AM1, and the H2 receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p < 0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H2 receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H2 receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.