Interaction between erythromycin and the benzodiazepines diazepam and flunitrazepam

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double-blind, cross-over studies. Healthy volunteers ingested erythromycin for one week 500 mg t.i.d. On the 4th day they ingested a single 5 mg dose of diazepam (6 subjects, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively. Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam. In Study 1 erythromycin increased the area under the diazepam plasma concentration-time curve [AUG (0-42 hr)] by 15% (P<0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P<0.05). The median peak concentration (C-max and the half-life (t(1/2)) of diazepam were increased but they did not change significantly (P=0.17 and 0.12, respectively). Plasma N-desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P<0.05). In Study 2 the AUC (0-42 hr) of flunitrazepam was increased by 25% (P<0.05) during the erythromycin treatment. The t(1/2) of flunitrazepam increased significantly (P<0.05), but the C-max remained unchanged. The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin. These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam. The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.