erythromycin-estolate and Body-Weight

Erythromycin and some other macrolide antibiotics can first induce a cytochrome P-450 isozyme similar to the one induced in rats by pregnenolone-16 alpha-carbonitrile and then inhibit it by forming a stable cytochrome P-450-metabolite complex. The purpose of this study was to compare azithromycin, a novel 15-membered ring azalide, and erythromycin estolate for the potential to cause hepatic microsomal enzyme induction and inhibition in Sprague-Dawley rats. The daily oral administration of 800 mg of erythromycin estolate per kg for 7 days resulted in statistically significant elevations of NADPH-cytochrome c reductase, erythromycin N-demethylase (3.2-fold), and total cytochrome P-450 content. Approximately 40% of cytochrome P-450 was complexed with erythromycin metabolite. In contrast, the daily administration of 200 mg of azithromycin per kg for 7 days caused significant elevations of N-demethylase (2.5-fold) only and did not produce any increases in total cytochrome P-450 content or NADPH-cytochrome c reductase. No complexed cytochrome P-450 was detected in the azithromycin-dosed rats despite liver concentrations of azithromycin that were 118 times greater than the liver concentrations of erythromycin estolate in erythromycin estolate-dosed rats. Although the short-term oral administration of azithromycin produced hepatic accumulation of the drug and elevated azithromycin demethylase activity, there was no other evidence of hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex formation. In contrast to erythromycin estolate, azithromycin is not expected to inhibit its own metabolism or that of other drugs via this pathway.

Topics: Animals; Azithromycin; Body Weight; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Erythromycin; Erythromycin Estolate; Liver; Male; Micrococcus; Microsomes; Microsomes, Liver; Mixed Function Oxygenases; NADPH-Ferrihemoprotein Reductase; Pregnenolone Carbonitrile; Rats; Rats, Inbred Strains

The effects of a new fluorinated macrolide (P-0501A) on drug metabolizing enzymes of rat liver were compared with three erythromycins--the base, the stearate and the estolate--after 7 days of dosing (1.36 mmol/kg po daily). The three erythromycins induced the synthesis of microsomal enzymes, but the products of their metabolism inactivated cytochrome P-450 in the order base less than or equal to stearate less than estolate. N-Demethylation of erythromycin and aminopyrine increased, while O-demethylation of 4-nitroanisole was reduced and hydroxylation of aniline was not changed after in vivo treatment. Pentobarbital sleeping time was prolonged and liver glutathione levels were lower in treated rats than in controls. In contrast to the three erythromycins, P-0501A did not induce the synthesis of microsomal enzymes, did not form an inactive complex with cytochrome P-450 and did not affect mono-oxygenase activities or pentobarbital narcosis.

Topics: Administration, Oral; Aminopyrine N-Demethylase; Animals; Body Weight; Cytochrome b Group; Cytochrome P-450 Enzyme System; Cytochromes b5; Drug Interactions; Enzyme Induction; Erythromycin; Erythromycin Estolate; Glutathione; Male; Microsomes, Liver; NADPH-Ferrihemoprotein Reductase; Organ Size; Pentobarbital; Rats; Sleep