H2-RECEPTOR ANTAGONISTS AND HEPATIC DRUG DISPOSITION

The effect of 4 H2-receptor antagonists (cimetidine, burimamide, oxmetidine and ranitidine) on antipyrine elimination was studied in the isolated perfused rat liver. The 1st 3 drugs are substituted imidazoles, whereas ranitidine contains a furanyl nucleus. Isolated livers were perfused using a 100-ml, recycling, constant flow circuit for 4 h. Antipyrine elimination was studied with or without an H2-receptor antagonist present. In all experiments, antipyrine concentrations declined monoexponentially. In control experiments (no other drug present), antipyrine clearance was 32.5 .+-. 9.0 ml/h. This was greatly reduced in the presence of cimetidine (clearance = 10.1 .+-. 0.8 and 5.8 .+-. 1.5 ml/h after 1 and 5 mg doses, P < 0.001) and burimamide (4.5 .+-. 0.6 and 3.0 .+-. 1.7 ml/h, P < 0.001). Neither oxmetidine nor ranitidine significantly altered antipyrine pharmacokinetics. Apparently, the inhibitory effect on hepatic mixed-function oxidases is rapid in onset, independent of H2-receptor antagonist activity and is not an inevitable consequence of the presence of an imidazole nucleus.