Erythromycin absorption

The acid-instabihty of erythromycin makes it susceptible to degradation in the stomach to intramolecular cyclization products lacking antimicrobial activity. Relatively water-insoluble, acid-stable salts, esters, and/or formulations have therefore been employed to protect erythromycin during passage through the stomach, to increase oral bioavakabihty, and to decrease the variabiUty of oral absorption. These various derivatives and formulations also mask the very bitter taste of macroHdes. 

A complication here, however, is noted with those drugs that exhibit a limited chemical stability in either acidic or alkaline fluids. Since the rate and extent of degradation is directly dependent on the concentration of drug in solution, an attempt is often made to retard dissolution in the fluid where degradation is seen. There are preparations of various salts or esters of drugs (e.g., erythromycin) that do not dissolve in gastric fluid and thus are not degraded there but which dissolve in intestinal fluid prior to absorption. A wide variety of chemical derivatives are used for such purposes. 

Figure 3 illustrates a situation in which this may not be true. When 250 mL of water was taken with erythromycin tablets, the extent of absorption was much greater than when the tablets were taken with only 20 mL of water. In the latter case, dissolution probably did not occur under sink conditions. Hence, the dissolution rate decreased, and it appears that not all of the erythromycin had a chance to dissolve in the GIT. Note than the dissolution was not, however, the ratedetermining step in absorption, since the time to reach the peak concentration was the same in all situations. 

The infrared spectrum of erythromycin is commonly used for its identification. Figure 2 shows the spectrum of a 75 mg./ml. chloroform solution. The bands at 1685 and 1730 cm- are due to the ketone carbonyl and the lactone carbonyl, respectively. The absorption peaks between 1000 and 1200 cm-1 are due to the ethers and amine functions. The CH2 bending is evidenced by peaks between 1340 and 1460 cm-, and alkane stretching peaks appear between 2780 and 3020 cm-. Hydrogen bonded OH and water appear as bands between 3400 and 3700 cm-1. 

Metoclopramide, neurolepics and erythromycin increases gastrointestinal motility can give pain and affect absorption of nutrition s... 

Ezetimibe/Simvastatin (Vytorin) [Antilipemic/HMG CoA Reductose Inhibitor] Uses H rp cholest olemia Action X Absorption of cholesterol phytost ol w/ HMG-CoA reductase inhibitor Dose 10/10-10/80 mg/d PO w/ cyclosporine or danazol 10/10 mg/d max w/ amio-darone or verapamil 10/20 mg/d max -1- w/ sev e renal insuff Caution [X, -] w/ CYP3A4 inhibitors (Table VI-8), gemfibrozil, niacin >lg/d, danazol, amiodarone, verapamil Contra PRG/lactation livCT Dz, t LFTs Disp Tabs SE HA, GI upset, myalgia, myopathy (muscle pain, weakness, or tendOTiess w/ CK 10 x ULN, rhab-domyolysis), Hep, Infxn Interactions t Risk of myopathy W7 clarithromycin, erythromycin, itraconazole, ketoconazole EMS None OD Sxs unknown symptomatic and supportive... 

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. 

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against M leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. 

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. 

In liquid chromatographic analysis of macrolides and lincosamides, most popular is the ultraviolet detector (Table 29.4). Tylosin, tilmicosin, spiramycin, sedecamycin, and josamycin exhibit relatively strong ultraviolet absorption, but erythromycin, lincomycin, pirlimycin, and oleandomycin show extremely weak absorption in the ultraviolet region. Hence, detection at 200-210 nm has been reported for the determination of lincomycin (146). However, a combination of poor sensitivity and interference from coextractives necessitated extensive cleanup and concentration of the extract. Precolumn derivatization of pirlimycin with 9-fluorenylmethyl chloroformate has also been described to impart a chromophore for ultraviolet detection at 264 nm (140). 

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. 

Dey, S., Gunda, S., Mitra, A. K. Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption. J. Pharmacol. Exptl. Then 2004, 311, 246-256. 

Administration The erythromycin base is destroyed by gastric acid thus either enteric coated tablets or esterified forms are administered. All are adequately absorbed on oral administration. Clarithromycin and azithromycin are stable to stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin. Intravenous administration of erythromycin is associated with a high incidence of thrombophlebitis. 

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