Interaction of dihydroergotamine and triacetyloleandomycin in the minipig.
The kinetics of unchanged DHE and of the sum of parent drug and metabolites under the effect of acute TO exposure were investigated by comparing the areas under the plasma concentration-time curves after oral, intravenous and hepatoportal administration in minipigs. While TO (500 mg p.o. 15 min. before DHE) caused only a slight increase of plasma levels of parent drug or the sum of parent drug and metabolites after an intravenous dose of 1 mg DHE, there was an important and significant increase of the 0-24 hrs AUC's after administration of (10 mg) oral or (1 mg) hepatoportal DHE. This finding strongly suggests that the interaction TO and DHE occurs at the hepatic site. However, under these experimental conditions, the metabolism of DHE does not seem to be modified by TO administration, an indication that the mechanism of the interaction with TO could be an inhibition of the biliary excretion of DHE and DHE metabolites and/or a release of DHE and metabolites from hepatic binding sites.