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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.

Administration, Oral↗
PubMed1985

Triacetyloleandomycin as inducer of cytochrome P-450 LM3c from rabbit liver microsomes.

A cytochrome P-450 LM3 isozyme has been isolated and purified to electrophoretic homogeneity from liver microsomes of New Zealand white rabbits treated with TAO. On the basis of N-terminal sequence analysis and Ouchterlony double diffusion experiments, this isozyme appeared to be closely related to P-450 LM3c isolated from control animals and was designated LM3c (TAO). Anti LM3c (TAO) IgG totally inhibited both erythromycin demethylase and P-450-TAO metabolite complex formation, two monooxygenase activities specifically stimulated by TAO in liver microsomes from male and female rabbits. Moreover, immunoquantitation experiments showed that the level of LM3c (TAO) was increased 10-15 times above control values in liver microsomes from TAO treated male and female rabbits. We conclude that an isozyme identical or closely related to LM3c is the major form of P-450 induced by TAO in rabbit liver microsomes.

Animals↗