Macrolide antibiotics metabolites

Macrolide antibiotics, in some instances, may be considered as hydroxy acid derivatives. In addition, many of them have carbohydrates attached, often with unique structural features, as illustrated by erythromycin (20).53 Although some of these antibiotics are semi-synthetic, all are derived by a fermentation process where the antibiotic is formed as a secondary metabolite. This approach, of course, alleviates the need to perform complex carbohydrate chemistry (see Chapter 19). 

Several 16-membered macrolides form metabolites which retain antimicrobial activity. As discussed above, 3"-esters such as rokitamycin and miokamycin produce prolonged concentrations of antibiotic in vivo due to the facile 3"- to 4"-0-acyl migration that follows enzymatic removal of the original 4 -ester [34, 269, 270], Following a different approach to overcome the lability of 4"-esters, specific 4"-0-acyl derivatives of tylosin were selected from the series of esters (15) based upon their greater stability toward liver enzymes [80], Although esterases play the most prominent role in metabolism of 16-membered macrolides, other mechanisms such as oxidative hydroxylation, A-demethylation, reduction, and hydrolysis of sugars have been reported for various compounds [91, 96, 115, 259, 270-272]. 

Some of the macrolide antibiotics have been reported to inhibit the clearance of disopyramide (SEDA-21, 200) (SEDA-22, 207), resulting in serious dysrhythmias or hypoglycemia. The mechanism of this interaction is presumed to be inhibition of dealkylation of disopyramide to its major metabolite, mono-A-dealkyldisopyramide. For example, in human liver microsomes the macrolide antibiotic troleandomycin significantly inhibited the mono-A-dealkylation of disopyramide enantiomers by inhibition of CYP3A4 (34). This interaction can result in serious dysrhythmias or other adverse effects of disopyramide. 

Tilmicosin, (20-deoxo-20-(3,5-dimethylpiperidin-l-yl)-desmycosin) is a new macrolide antibiotic which is being developed for treatment of bovine respiratory disease by single subcutaneous injection into cattle. Excretion, tissue residue, and metabolism studies were conducted with " C-tilmicosin-treated cattle and rats. Radioactivity was excreted primarily in the feces after parenteral dosing of cattle and oral dosing of rats. Among edible tissues from treated cattle, liver and kidney contained the highest concentrations of radioactivity. The most abundant metabolite was N-desmethyl tilmicosin. Comparative metabolism studies with cattle and rats indicated that the pattern of metabolism was the same for both species. 

R—N(CH3)2. This amine is demethylated and oxidized by cytochrome P-450 into a metabolite, probably the nitroso derivative (R—N=0), which forms a stable, inactive complex with the iron (Fe ) of cytochrome P-450 [115]. This complex prevents the enzyme from metabolizing other drugs any further [116]. These inactive complexes have been found in patients taking erythromycin. However, not all macrolides have been associated with the formation of these complexes [117]. The enzyme CYP3A4 appears to be most susceptible to inhibition by the macrolide antibiotics. This binding to and reduction in CYP3A4 activity is the... 

Delaforge, M., Jaouen, M., and Mansuy, D. (1983). Dual effects of macrolide antibiotics on rat liver cytochrome P-450. Induction and formation of metabolite complexes A structure-activity relationship. Biochem. Pharmacol. 32, 2309-2318. 

Jurima-Romet, M. Crawford, K. Cyr, T. Inaba, T. Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab.Dispos., 1994, 22, 849—857 [extracted metabolites microsomal incubations rat column temp 35 LOQ 92 nM] von Moltke, L.L. Greenblatt, D.J. Duan, S.X. Harmatz, J.S. Shader, R.I. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J.Clin.Pharmacol., 1994, 34, 1222—1227 [clomipramine (IS) microsomal incubations]... 

Another aspect of P450 3A4 regulation involves degradation. Troleandomycin, erthyromycin, and some related amine macrolide antibiotics form metabolite complexes (C-nitroso iron, R-N= 0 Fe) and inactive protein accumulates " These studies have relevance to in vivo P450 3A4 inhibition by these drugs. 

The macrolide antibiotic tulathromycin also has residue limits defined in terms of a marker residue obtained by the hydrolysis of a range of metabolites. Again, analysis of incurred tissues indicates that the marker residue is not a major component of the residues present. ... 

---