Erythromycin Subject

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macroHdes some of the derivatives ate being commercially launched (116). 

A combination of neomycin and nonabsorbable erythromycin base given orally prior to colorectal surgery can markedly reduce the incidence of postoperative wound infection. Orally administered neomycin is sometimes used to suppress the facultative flora of the gut in patients with hepatic encephalopathy. It is unclear how this improves coma, but one theory is that it reduces systemic absorption of the bacterial metabo-htes that allegedly cause hepatic encephalopathy. Although more than 95% of an oral dose of neomycin is excreted unchanged in the stool of normal subjects, the bioavaUabUity of neomycin may be much higher in patients with an abnormal gastrointestinal mucosa. 

Verapamil, diltiazem, erythromycin, and itraconazole all increase the plasma concentration of buspirone. The plasma concentration is decreased almost 10-fold by rifampicin. Grapefruit juice increases the overall subjective effect of the drug (Mahmood and Saha-jwalla, 1999). 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macrolides some of the derivatives are being commercially launched. Derivatives of erythromycin and oleandomycin include 2-U-nee ly I erythromycin (C331129NO t. 2 -O-propionylerythromycin (QoHtiNOm), erythromycin ethyl carbonate (C/0H71NO15), erytliromydn ethyl succinate (C 3H75NOi2), tn-O-acetyloleandomycin (C4iHc7NOi5), erythromycin-11,12-carbonate... 

Pretreatment with octreotide enhanced the gastric prokinetic effects of erythromycin in eight healthy subjects, suggesting that octreotide may be clinically useful in patients with tachyphylaxis to this effect of erythromycin (55). 

Athanasakis E, Chrysos E, Zoras OJ, Tsiaoussis J, Karkavitsas N, Xynos E. Octreotide enhances the accelerating effect of erythromycin on gastric emptying in healthy subjects. Aliment Pharmacol Ther 2002 16(8) 1563-70. 

Freeman J, Martell R, Carrufhers S, et al. Cyclosporin-erythromycin interaction in normal subjects. Br J Clin Pharmacol 1987 23 776-778. 

Craig PI, Tapner M, Farrell GC. Interferon suppresses erythromycin metabolism in rats and human subjects. Hepatology 1993 17 230-235. 

Orlando R, Piccoli P, De Martin S, et al. (2003) Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function. Br J Clin Pharmacol 55 86-93. 

Following single oral doses of 250 mg, 500 mg, and 1 g of a preparation containing enteric-coated pellets of erythromycin base to 23 subjects, mean peak serum concentrations of 1.9, 3.8, and 6.5 pg/ml, respectively, were attained in about 2 hours. After a single oral dose of 500 mg of erythromycin stearate to the same subjects, a mean peak serum concentration of 2.9 pg/ml was attained in about 2 hours (K. Josefsson et ai, Br. J. din. Pharmac., 1982,13, 685-691). 

Following oral administration of 250 mg of erythromycin four times a day to 16 subjects, maximum and minimum steady-state plasma concentrations of 1.7 and 0.45 pg/ml were reported on the third day, compared to 1.34 and 0.58 pg/ml respectively, following repeated oral administration of erythromycin estolate (A. R. DiSanto et al., J. din. Pharmac., 1980, 20, 437-443X... 

Cardiac effects were reported from early experimental work using very high doses of ebastine, but they are not believed to be clinically relevant in normal use. In one study serial electrocardiograms showed no changes with doses up to the maximum used (30 mg). Ebastine in doses up to five times the recommended therapeutic dose did not cause clinically relevant changes in QTc interval in healthy subjects (2). Co-administration of ebastine with ketoconazole or erythromycin did not lead to significant changes in the QTc interval (3,4). 

The effects of erythromycin, an inhibitor of CYP3A4, on the pharmacokinetics of lidocaine have been studied in nine healthy volunteers. Steady-state oral erythromycin had no effect on the plasma concentration versus time curve of lidocaine after intravenous administration, but erythromycin increased the plasma concentrations of the major metabolite of lidocaine, MEGX (78). It is not clear what the interpretation of these results is, particularly since the authors did not study enough subjects to detect what might have been small but significant changes in various disposition parameters of lidocaine and did not report unbound concentrations of Udocaine or its metabolites. However, whatever the pharmacokinetic explanation, the clinical relevance is that one would expect that erythromycin would potentiate the toxic effects of lidocaine that are mediated by MEGX. 

Erythromycin estolate differs from other forms of erythromycin in that it is extremely stable to acid hydrolysis.5 Erythromycin liberated from the ester by mild alkaline hydrolysis is subject to rapid decomposition in strongly acid solutions. Kavanagh has stated that deterioration of erythromycin increases with an increase in temperature and decreases with an increase in pH up to 8.0. Buffered aqueous solutions of erythromycin base are quite stable at this pH. Acetone solutions of the ester form are stable, while acetone solutions of the propionyl erythromycin lauryl sulfate preparation are not. Powders and dry formulations are stable for at least five years. Liquid preparations become unacceptable after 2 years due to undesirable taste. 

Modern spectroscopic techniques have revolutionized compound identification and quantification. Only a few decades ago, identification of a structurally complex natural product would require multigram quantities of isolated material, which would then be subjected to series of derivatization and degradation experiments, aiming to deduce the unknown s structure from that of resulting derivatives or fragments that may represent known compounds. As a result of the tremendous advances in sensitivity and resolution of NMR spectroscopy over the past 30 years, identification of microgram quantities of new compounds has now become routine. For example, the structure of the polyketide antibiotic, erythromycin (1), was identified in 1957 only after extensive chemical and spectroscopic studies based on multigram amounts of isolated compound.1-3 By the time its... 

Birkett et al. [24] reported that the dose-normalized mean maximal plasma concentration for roxithromycin in 12 healthy subjects was approximately 5-fold greater than that for erythromycin and, as a result, the normalized AUC was 27-fold greater for roxithromycin than for erythromycin. The elimination half-lives (7 i/2) of roxithromycin and erythromycin are different, ranging from 10 to 13 hr for roxithromycin and from 2 to 3 hr for erythromycin after single oral doses (roxithromycin 150, 300,450 mg erythromycin 250,500,1000 mg) [23]. 

---