Pharmacokinetic Drug Interactions of Macrolides

Abstract

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)

PhosphonateO-Deethylation of [4-(4-Bromo-2-Cyano-Phenylcarbamoyl) Benzyl]-Phosphonic Acid Diethyl Ester, a Lipoprotein Lipase-Promoting Agent, Catalyzed by Cytochrome P450 2C8 and 3A4 in Human Liver Microsomes

“…CYP3A is the major P450 subfamily in the human liver and intestine and is involved in the metabolism of a variety of pharmaceutical agents that are metabolized by P450. CYP3A enzymes have been reported to be involved in interactions with several drugs such as macrolides, ketoconazole, and cyclosporin (Pichard et al, 1990;Periti et al, 1992). In addition, CYP2C8 that catalyzes the oxidative reaction of selective substrates plays an important role as the low-K m component in the human liver.…”

Histological features of acute hepatitis after imatinib mesylate treatment

“…Roxithromycin has been shown to be an inhibitor of cytochrome P450 enzyme CYP3A4, although it is not as potent as erythromycin. 8 As imatinib is a competitive inhibitor of the cytochrome P450 enzymes CYP3A4/5, CYP2C9 and CYP2D6, the administration of roxithromycin is expected to result in increased levels of imatinib, thus increasing its toxicity. Both patients had an imatinib 're-challenge' immediately followed by recurrence of biochemical abnormalities, thereby reinforcing the implication of imatinib in the hepatic dysfunction.…”

The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers

“…It is strongly inhibited by clarithromycin and erythromycin but not by azithromycin. 2,3 In the presence of an inhibitor of this isoenzyme, drugs that require cytochrome P450 3A4 for their metabolism will accumulate, potentially leading to toxicity. 4,5 Cytochrome P450 3A4 has many substrates of clinical relevance, but the calcium-channel blockers are of particular importance.…”