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Drug Metab Dispos. 2000 Dec;28(12):1391-3.
Effects of macrolide antibiotics on CYP3A expression in human and rat hepatocytes: interspecies differences in response to troleandomycin.
Ledirac N, de Sousa G, Fontaine F, Agouridas C, Gugenheim J, Lorenzon G, Rahmani R.
Laboratoire de Pharmacotoxicologie INRA, Antibes, France.
The effects of various macrolide antibiotics [triacetyloleandomycin (TAO), clarithromycin, azithromycin, roxithromycin, erythromycin base] and the new ketolide HMR3004 on CYP3A expression were evaluated in human and rat hepatocytes. Cells were treated for 3 days with nontoxic concentrations of the drugs, and CYP3A induction was assessed through midazolam hydroxylase activity and Western and Northern blot analyses. In rat hepatocytes, no induction of CYP3A1 expression was observed following exposure to macrolides, even to erythromycin base and TAO (well known in vivo CYP3A1 inducers), whereas dexamethasone and phenobarbital were confirmed to induce this enzyme. In contrast, treatment of fresh and thawed human hepatocytes with TAO, produced an increase of midazolam hydroxylation (4-fold over control). This result was in agreement with the high amount of CYP3A4 protein and mRNA revealed by Western and Northern blot analyses. Other tested macrolides had no induction effect on CYP3A expression. These results confirmed the interspecies variability of CYP3A regulation in hepatocytes and raised the question of its mechanism of induction by macrolides in human liver.
online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11095572&dopt=Abstract
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