INTERACTION BETWEEN ERYTHROMYCIN AND THE BENZODIAZEPINES DIAZEPAM ANDFLUNITRAZEPAM

The effect of erythromycin on the pharmacokinetics and pharmacodynamic s of diazepam and flunitrazepam was investigated in two randomized, do uble-blind, cross-over studies. Healthy volunteers ingested erythromyc in 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 flunitrazepa m (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 6 3% (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 significantl y (P=0.17 and 0.12, respectively). Plasma N-desmethyldiazepam concentr ations 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 fluni trazepam increased significantly (P<0.05), but the C-max remained unch anged. The psychomotor effects of diazepam or flunitrazepam were not c hanged significantly by erythromycin. These pharmacokinetic interactio ns can be explained by the reduced metabolic elimination of diazepam a nd flunitrazepam. The interactions of erythromycin with diazepam and f lunitrazepam seem to be slight and of limited clinical significance on ly.