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Macrolide antibacterials. Drug interactions of clinical significance
1University Children's Hospital, Munich, Germany.
Abstract:
Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine.
Insights
Macrolide antibiotics can cause drug interactions by affecting drug metabolism via cytochrome P-450 IIIA4 (CYP3A4) inhibition. Classifying macrolides by their CYP3A4 affinity helps predict and manage these adverse effects.
Area of Science:
- Pharmacology
- Drug Metabolism
- Drug Interactions
Background:
- Macrolide antibiotics can cause adverse drug interactions.
- These interactions often occur due to inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes.
- Other mechanisms include effects on enteric flora and enhanced gastric emptying.
Purpose of the Study:
- To classify macrolide antibiotics based on their potential to cause pharmacokinetic drug interactions.
- To identify macrolides with high, low, or no propensity for CYP3A4-mediated drug interactions.
- To highlight common and rare drug interactions involving macrolides.
Main Methods:
- Classification of macrolides into three groups based on CYP3A4 affinity.
- Review of known drug interactions with macrolide antibiotics.
- Identification of frequently encountered and rare interactions.
Main Results:
- Group 1 macrolides (e.g., erythromycin) significantly inhibit CYP3A4 and increase drug interaction risk.
- Group 2 macrolides (e.g., clarithromycin) rarely cause interactions.
- Group 3 macrolides (e.g., azithromycin) do not inactivate CYP3A4 and pose minimal interaction risk.
- Common interactions involve carbamazepine, cyclosporin, terfenadine, astemizole, and theophylline.
Conclusions:
- Macrolide classification by CYP3A4 affinity is crucial for predicting drug interaction potential.
- Monitoring drug concentrations is recommended when combining macrolides with interacting drugs.
- Azithromycin and related macrolides are safer choices regarding CYP3A4-mediated interactions.