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Effects of clarithromycin on cytochrome P-450. Comparison with other macrolides
M Tinel1, V Descatoire, D Larrey
1Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale U 24), Hôpital, Beaujon, Clichy, France.
Abstract:
Repeated administration of clarithromycin (0.5 mmol.kg-1 p.o. daily for 5 days) to rats increased markedly the same cytochrome P-450 isoenzyme (P-450p) as that induced by troleandomycin. Clarithromycin, however, did not form cytochrome P-450 Fe(II)-metabolite complexes in vitro with microsomes from clarithromycin-treated rats or in vivo after repeated doses of clarithromycin. Nevertheless, clarithromycin formed cytochrome P-450 Fe(II)-metabolite complexes with microsomes from dexamethasone-treated rats in vitro, or after administration to dexamethasone-treated rats in vivo. Similar effects were observed with roxithromycin. In contrast, erythromycin and troleandomycin formed metabolic complexes when given alone, whereas josamycin, midecamycin and spiramycin did not form complexes, even in dexamethasone-treated rats. We conclude that clarithromycin and roxithromycin induce cytochrome P-450p, but do not form complexes with this isoenzyme, although they do form complexes with other glucocorticoid-inducible isoenzymes. We propose that macrolides may be classified into three groups, those forming complexes when given alone (e.g., erythromycin and troleandomycin), those forming complexes only in glucocorticoid-pretreated rats (clarithromycin and roxithromycin) and those not forming complexes (josamycin, midecamycin and spiramycin).
Insights
Clarithromycin and roxithromycin induce a specific liver enzyme (cytochrome P-450p) but do not form harmful complexes. This macrolide antibiotic classification helps predict drug interactions.
Area of Science:
- Pharmacology
- Drug Metabolism
- Biochemistry
Background:
- Macrolide antibiotics are widely used, but their interactions with liver enzymes like cytochrome P-450 can affect drug efficacy and safety.
- Specific macrolides are known to induce cytochrome P-450 isoenzymes, potentially leading to drug-drug interactions.
- Understanding how different macrolides interact with cytochrome P-450 isoenzymes is crucial for predicting and managing these interactions.
Purpose of the Study:
- To investigate the induction and complex-formation properties of clarithromycin and roxithromycin with cytochrome P-450 isoenzymes in rats.
- To compare the effects of clarithromycin and roxithromycin with other macrolides (erythromycin, troleandomycin, josamycin, midecamycin, spiramycin) on cytochrome P-450.
- To propose a classification of macrolides based on their ability to form cytochrome P-450 Fe(II)-metabolite complexes.
Main Methods:
- Repeated oral administration of clarithromycin (0.5 mmol/kg daily for 5 days) to rats.
- In vitro and in vivo studies using rat liver microsomes and drug administration to assess cytochrome P-450 Fe(II)-metabolite complex formation.
- Comparison of clarithromycin and roxithromycin effects with other macrolides, including those pretreated with dexamethasone.
Main Results:
- Clarithromycin and roxithromycin induced the same cytochrome P-450 isoenzyme (P-450p) as troleandomycin.
- Clarithromycin and roxithromycin did not form cytochrome P-450 Fe(II)-metabolite complexes when administered alone but did so in dexamethasone-treated rats.
- Erythromycin and troleandomycin formed complexes when given alone, while josamycin, midecamycin, and spiramycin did not form complexes even with dexamethasone pretreatment.
Conclusions:
- Clarithromycin and roxithromycin induce cytochrome P-450p but do not form complexes with it, though they can complex with other glucocorticoid-inducible isoenzymes.
- Macrolide antibiotics can be classified into three groups based on their complex-forming abilities: those forming complexes alone, those forming complexes only after glucocorticoid pretreatment, and those not forming complexes.
- This classification aids in understanding and predicting potential drug interactions associated with macrolide antibiotic use.