INHIBITION OF NIFEDIPINE METABOLISM IN DOGS BY ERYTHROMYCIN - DIFFERENCE BETWEEN THE GUT WALL AND THE LIVER

The purpose of this study was to evaluate possible interaction of nife dipine with erythromycin or rokitamycin in the intestinal mucosa. Male beagle dogs were orally administered nifedipine (10 mg), with or with out oral pre-medication with erythromycin (300 mg), and 300 mg erythro mycin or rokitamycin twice a day for 3 days. The experiments were of r andomized cross-over design with a two-week wash-out period between do sing regimens. Erythromycin pre-medication for 3 days resulted in a si gnificant increase in the area under the serum nifedipine concentratio n-time curve (AUG), whereas the curve for one nifedipine metabolite (M -2) decreased significantly. When the effects of erythromycin on the m etabolism of nifedipine were studied using dog liver microsomes it was found that erythromycin significantly inhibited formation of M-2 but not of the metabolite M-l. These results indicate that formation of M- 2 from M-1 in the liver might be reduced by erythromycin pre medicatio n. To avoid possible metabolism in the gut, the dogs were then adminis tered 8 mg nifedipine into the peritoneal cavity, with or without mult iple dose pre-treatment with erythromycin for 3 days. After intraperit oneal administration of nifedipine, the maximum concentration (C-max) of nifedipine increased significantly. After pre administration of ery thromycin the relative bioavailability of nifedipine after oral admini stration was increased compared with injection into the peritoneal cav ity. In-vitro study using rat intestinal microsomes and the in-vivo ra t intestinal loop technique also showed that pre-administration of ery thromycin inhibits nifedipine metabolism in the small intestine.