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In vitro effects of racemates, separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes.
- Source :
-
Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 1999 Jun; Vol. 29 (6), pp. 595-601. - Publication Year :
- 1999
-
Abstract
- 1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed Km and Vmax, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine Ki of metoprolol alpha-hydroxylation and O-demethylation were 3.4 and 5.8 microM respectively, whereas those of halofantrine were 0.15 and 0.32 microM respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine. The potency order for metoprolol metabolism inhibition was halofantrine >> mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.
- Subjects :
- Animals
Antimalarials chemistry
Biotransformation drug effects
Male
Mefloquine chemistry
Metoprolol antagonists & inhibitors
Microsomes, Liver drug effects
Phenanthrenes chemistry
Rats
Rats, Sprague-Dawley
Stereoisomerism
Antimalarials pharmacology
Mefloquine pharmacology
Metoprolol pharmacokinetics
Microsomes, Liver metabolism
Phenanthrenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0049-8254
- Volume :
- 29
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Xenobiotica; the fate of foreign compounds in biological systems
- Publication Type :
- Academic Journal
- Accession number :
- 10426558
- Full Text :
- https://doi.org/10.1080/004982599238416