Clarithromycin elimination

Roxithromycin, clarithromycin, azithromycin and dirithromycin are more recently developed macrolides with similar antimicrobial activity to erythromycin. However they are better absorbed, have longer elimination half-lives and lower incidence of gastrointestinal side-effects. Azithromycin and... 

Erythromycin and azithromycin are excreted primarily in active form in bile, with only low levels found in urine. Clarithromycin is metabolized to the biologically active 14-OH metabolite and is eliminated largely by the kidney. The half-life of erythromycin is approximately 1.4 hours, whereas the half-life of clarithromycin is 3 to 7 hours and that of azithromycin approaches 68 hours. 

Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. A portion of active drug and this major metabolite is eliminated in the urine, and dosage reduction (eg, a 500-mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. Clarithromycin has drug interactions similar to those described for erythromycin. 

Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD. Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol 1999 103(6) 1031-5. 

Excretion Erythromycin and azithromycin are primarily concentrated and excreted in an active form in the bile. Partial reabsorption occurs through the enterohepatic circulation. In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver and it is recommended that dosage be adjusted in patients with compromised renal function. 

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

Verapamil is both a snbstrate and an inhibitor of CYP3A4, which is inhibited by clarithromycin and erythromycin. Giving these macrolide antibiotics dnring verapamil therapy is likely to rednce the first-pass metabolism of verapamil, increase its systemic availability, and impair its elimination. In patients taking this combination, verapamil should be started in a low dosage and its hemodynamic effects should be monitored closely. 

Elimination All macrolides are hepatically eliminated. Clarithromycin is hepatically activated to the 14-OH metabolite. Vk erythromycin < clarithromycin < azithromycin. 

FIGURE 2.2 An example of fine-tuning of pharmacologically active chemicals Erythromycin 2 -ethylsuccinate and clarithromycin are semisynthetic derivatives of the macroUde antiinfective erythromycin. The small molecular change in the former leads to the elimination of bitterness which is important as this class of drugs is often used in pediatrics and administered as a syrup. In the latter, because hemiketal formation is no longer possible (arrow), clarithromycin is stable in the acidic milieu of the stomach (pH 2). 

Clarithromycin undergoes both hepatic and renal elimination. After a single 250-mg dose of radioactive clarithromycin in healthy subjects, 28% of the radioactivity was detected in the urine within 12 hr, and 38% was detected within 5 days. Fecal excretion averaged 40% of a dose. Urinary excretion was proportionately... 

Owing to its long elimination half-life (3 days), weekly administration of azithromycin has proved to be equivalent to daily administration of clarithromycin when used for prophylaxis against M avium complex in AIDS patients. The answer is (A). 

Nelfinavir mesylate is a peptidomimetic drug that is effective in HIV-1 and HIV-2 wild-type and ZDV-resistant strains, with median effective dose concentrations ranging from 9 to 60 nM (95% effective dose, 0.04 mg/mL) (98). After IV administration, the elimination half-life of nelfinavir was approximately 1 hour. In combination with D4T, nelfinavir reduced HIV viral load by approximately 98% after 4 weeks. It is well tolerated when used with azole antifungals (ketoconazole, fluconazole, or itraconazole) or macrolide antibiotics (erythromycin, clarithromycin, or azithromycin) however, it causes diarrhea and other side effects common to nonnucleoside drugs. Following oral administration, nelfinavir peak levels in plasma ranged from 0.34 mg/mL (10 mg/kg in the dog) to 1.7 mg/mL (50 mg/kg in the rat). In the dog, nelfinavir was slowly absorbed, and bioavailability was 47%. The drug appeared to be metabolized in the liver, and the major excretory route was in feces. 

Caleium-ehaimel bloekers are metabolised in the gut wall and liver by the eytoehrome P450 CYP3A subfamily of isoenzymes, which are inhibited by erythromycin, clarithromycin, and telithromycin, so that in their presence a normal oral dose becomes in effect an overdose with its attendant adverse effects. Verapamil, erythromycin and possibly clarithromycin are also P-glycoprotein inhibitors, which may contribute to the pharmacokinetic interaction by reducing the elimination of the calcium-channel blocker, or by increasing macrolide absorption. ... 

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