In-vivo kinetics of the interaction between midazolam and erythromycin in rats, taking account of metabolic intermediate complex formation

To predict, quantitatively, the extent of drug interaction during repeated administration of a metabolic inhibitor, we analysed the effects of erythro mycin treatment under several regimens on the area under the concentration curve (AUC) of midazolam in rats. Midazolam was administered into the porta l vein 12 h after erythromycin treatment for 1, 2 or 3 days, or 12, 24, 36, 48, 72 and 96 h after erythromycin treatment for 4 days, and the plasma-co ncentration profiles of midazolam were analysed to assess the AUG. Moreover , the contents of total cytochrome P450 and inactive metabolic intermediate (MI) complex were simultaneously quantitated. While the AUC value of midaz olam was nor affected by the administration of erythromycin for 1 day, repe ated administration of erythromycin evoked an increase in AUC ratio (AVC in erythromycin-treated rats/AUC in vehicle-treated rats), which reached a ma ximum value of 1.99 at 12 h after 4 days' treatment with erythromycin. The total content of cytochrome P450 in liver microsomes was unaffected by eryt hromycin treatment. Although the MI complex was undetectable after 1 day's treatment with erythromycin, its content increased with duration of erythro mycin treatment, and the complex disappeared after the end of erythromycin treatment with a half-life of 12.3 h. In conclusion, the interaction betwee n erythromycin and midazolam could be well predicted when the formation of MI complex in the liver was taken into account.