H2–Receptor Antagonists and Hepatic Drug Disposition

Abstract

The effect of four H₂–receptor antagonists (Cimetidine, burimamide, oxmetidine, and ranitidine) on antipyrine elimination was studied in the isolated perfused rat liver. The first three drugs are substituted imidazoles, whereas ranitidine contains a furanyl nucleus. Isolated livers were perfused using a 100–ml, recycling, constant flow circuit for 4 hr. 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 per hr. This was greatly reduced in the presence of Cimetidine (clearance = 10.1 ± 0.8 and 5.8 ± 1.5 ml per hr after 1 and 5 mg doses, p < 0.001) and burimamide (4.5 ± 0.6 and 3.0 ± 1.7 ml per hr, p < 0.001). By contrast, neither oxmetidine nor ranitidine significantly altered antipyrine pharmacokinetics. These results indicate that 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.