Erythromycin bioavailability

The ester and ester salts of erythromycin are variably absorbed (18-45%) from the small intestine into the systemic circulation. Overall, erythromycin bioavailability depends upon the formulation administered with greatest bioavailability observed with the esto-late salt (Ilosone brand) and the least is observed with the base formulation. The bioavailability of the ethylsuccinate salt is highly variable. The majority of erythromycin formulations are more completely absorbed when administered in the fasting state whereas the ethylsuccinate salt is better absorbed... 

Intravenous antibiotic administration is the most common delivery method for surgical prophylaxis. Intravenous administration ensures complete bioavailability while minimizing the impact of patient-specific variables. Oral administration is also used in some bowel operations. Non-absorbable compounds like erythromycin base and neomycin are given up to 24 hours prior to surgery to cleanse the bowel. Note that oral agents are used adjunctively and do not replace IV agents. 

Schwarz, U. I., Gramatte, T., Krappweis, J., Oertel, R., Kirch, W., P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans, Int. J. Clin. Pharmacol. Ther. 2000, 38, 161-167. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

The Bioavailability Monograph for Erythromycin27 provides data for comparison of several manufacturers tablets of erythromycin. The criteria for bioavailability tests are discussed. 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluori-nation of erythromycin has been studied to ensure abetter stability in acidic medium and/or a better bioavailability. 

Other Fluorinated Antibiotic Drugs Flurithromydn is an erythromycin fluorinated atC-9. It was launched some years ago (Figure 8.21). Its preparation involves electrophilic fluorination of 8,9-anhydroerythromycin-6,9-hemiacetal or of erythronolide A with CFsOF, or with a N— F reagent (NFSI) (cf. Chapter 4). The advantage of the fluorine substitution is a better stability in acidic medium and an increased bioavailability. Two erythromycins fluorinated at C-14 are in clinical development HMR-3562 and HMR-3787). 

Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, oral anticoagulants, cyclosporine, and methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability. 

Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and therefore is free of the drug interactions that occur with erythromycin and clarithromycin. 

Pharmacokinetics attd Pharmacology. Older macrolides such as erythromycin exhibit relatively low serum concentrations, short in vivo half-hves, highly variable oral absorption, and low oral bioavailability. Improvements in these pharmacokinetic parameters have been accomplished for newer derivatives. The principal side effects of macrolides aie gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

Table 3 Measures of Cyclosporin Bioavailability and Hepatic Extraction After Oral Administration in the Presence or Absence of the CYP3A Inhibitors Ketoconazole and Erythromycin and the CYP3A Inducer Rifampin...

CALCIUM CHANNEL BLOCKERS MACROLIDES t plasma concentrations of felodipine when co-administered with erythromycin cases of adverse effects of verapamil (bradycardia and 1 BP) with both erythromycin and clarithromycin Erythromycin inhibits CYP3A4-mediated metabolism of felodipine and verapamil. Clarithromycin and erythromycin inhibit intestinal P-gp, which may t the bioavailability of verapamil Monitor PR and BP closely watch for bradycardia and 1 BP. Consider reducing the dose of calcium channel blocker during macrolide therapy... 

ATORVASTATIN, SIMVASTATIN MACROLIDES Macrolides may t levels of atorvastatin and simvastatin the risk of myopathy t over 10-fold when eiythromycin is co-administered with a statin Macrolides inhibit CYP3A4-mediated metabolism of atorvastatin and simvastatin. Also, erythromycin and clarithromycin inhibit intestinal P-gp, which may t the bioavailability of statins Avoid co-administration of macrolides with atorvastatin or simvastatin (temporarily stop the statin if the patient needs macrolide therapy). Manufacturers also recommend that patients be warned to look for the early signs of rhabdomyolysis when other statins are co-ingested with macrolides... 

COLCHICINE MACROLIDES Case reports of colchicine toxicity when macrolides were added Uncertain macrolides possibly inhibit hepatic metabolism of colchicine. Clarithromycin and erythromycin both inhibit intestinal P-gp, which may t bioavailability of colchicine Monitor FBC and renal function closely... 

AZITHROMYCIN, CLARITHROMYCIN, ERYTHROMYCIN THEOPHYLUNE 1. t theophylline levels 2. Possibly i eiythromycin levels when given orally 1. Inhibition of CYP2D6-mediated metabolism of theophylline (macrolides and quinolones -isoniazid not known) 2.1 bioavailability uncertain mechanism 1. Monitor theophylline levels before, during and after co-administration 2. Consider an alternative macrolide... 

ERYTHROMYCIN H2 RECEPTOR BLOCKERS -CIMETIDINE t efficacy and adverse effects of erythromycin, including hearing loss t bioavailability Consider an alternative antibiotic, e.g. clarithromycin. Deafness was reversible with cessation of erythromycin... 

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