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Cyclosporin A and erythromycin: A study of a drug interaction in the in situ perfused rat liver model

Using the in situ perfused rat liver model, the effect of erythromycin (Ery) on the disposition of cyclosporin A (CyA) and the major human metabolite, AMl, was investigated. Prior to perfusion experiments, oral dosing was carried out for three days on three groups of male Sprague—Dawley rats (300–350 g), involving pretreatment with water (control and H2O/Ery groups) or erythromycin (Ery oral group). On the fourth day, perfusion experiments took place using standard techniques, with the addition of 20 mg Ery to the H2O/Ery and Ery oral groups, and 2.5 mg CyA to all groups. Perfusate and bile samples were collected and assayed for CyA and AMl by HPLC. Results indicated that inhibition of CyA metabolism had occurred as the CyA concentration in perfusate was significantly higher in both Ery groups at all times compared to the control group, and the levels of AMl in both perfusate and bile were significantly lower than in the control group. There was also a marked reduction in the apparent metabolic clearance of CyA in the Ery groups. It was concluded that AMl production had been inhibited by Ery, the most likely mechanism being inhibition of the isoenzyme CYP3A with which Ery forms a stable complex.