Effects of macrolide antibiotics on drug metabolism in rats and in humans

Abstract

In rats, troleandomycin induces microsomal enzymes and promotes its own transformation into a metabolite forming an inactive complex with the iron (II) of cytochrome P-450; eventually, several monooxygenase activities are markedly reduced. In humans, troleandomycin also induces microsomal enzymes, and forms an inactive cytochrome P-450-troleandomycin metabolite complex; the clearance of antipyrine, that of theophylline, and that of methylprednisolone are markedly reduced. The concomitant administration of troleandomycin and other drugs may produce ischaemic accidents (ergotamine), cholestasis (oral contraceptives) and neurologic signs of intoxication (theophylline or carbamazepine). Qualitatively similar effects are produced, in rats and in humans, by erythromycin. These effects, however, are much weaker than those of troleandomycin. In humans, the clearance of antipyrine and that of theophylline are only slightly affected. Drug interactions have been reported in a few patients only. Josamycin and midecamycin do not form cytochrome P-450-metabolite complexes in rats. In humans, these macrolides do not inhibit the clearance of theophylline; midecamycin does not inhibit the clearance of antipyrine. Although a case of possible josamycin-ergotamine interaction has been reported, the role of josamycin may be questioned in this isolated instance. Midecamycin, or josamycin, might be preferred to other macrolides in those patients who must receive other drugs metabolized by cytochrome P-450.