Half-life macrolides

Clarithromycin is a macrolide that has a longer half-life than erythromycin so is administered twice daily. Clarithromycin is more active against Grampositive organisms than erythromycin. Clarithromycin may be used in combination with amoxicillin, for example, as part of triple therapy used for the eradication of Helicobacter pylori. 

Mecfianism of Action A macrolide that reversiblybindstobacterial ribosomes, inhibiting bacterial protein synthesis. Therapeutic Effect Bacteriostatic. Pharmacokinetics Variably absorbed from the GI tract (depending on dosage form used). Protein binding 70%-90%. Widely distributed. Metabolized in the liver. Primarily eliminated in feces by bile. Not removed by hemodialysis. Half-life 1.4-2 hr (increased in impaired renal function). 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

Interactions of macrolide antibiotics with midazolam are clinically important. Increases in serum concentration, AUC, and half-life, and a reduction in clearance have been documented (65). These changes can result in clinical effects, such as prolonged psychomotor impairment, amnesia, or loss of consciousness (66). 

Macrolides, particularly erythromycin and clarithromycin, inhibit CYP3A4. With erythromycin, the inhibition of CYP3A4 is non-competitive due to irreversible binding with the isoenzyme to form an inactive complex. Thus, unlike the case with inhibitors with a short half-life (e.g. cimetidine), the offset of inhibition is slow since new enzyme must be synthesized to replace the inactive complexes. Azithromycin, clarithromycin and erythromycin can prolong the Q-T interval and must not be co-administered with other Q-T-prolonging drugs. 

Azithromycin. Azithromycin is another recently developed macrolide antibiotic. After oral administration on an empty stomach, azithromycin is rapidly absorbed and widely distributed throughout the body. Because azithromycin has an extended half-life, once-daily dosing is effective and encourages patient compliance. 

Macrolide antibiotics are administered orally, but many of them exhibit low and/or variable degrees of oral absorption, low serum concentrations, and short half-lives. Consequently, selection of semi-synthetic derivatives for development has often been guided by greater oral bioavailability, longer half-life, and higher and more prolonged concentrations in serum and tissues. The clinical pharmacokinetic parameters of several 16-membered macrolides have recently been reviewed [58, 233, 234],... 

A second new semi-synthetic macrolide is tilmicosin, which inhibits a variety of animal pathogens including species of Pasteurella [295]. It is effective for both treatment and prophylaxis of respiratory infections in cattle after a single injection due to its long in vivo half-life and has been registered for the treatment of bovine respiratory disease [296-299]. Tilmicosin is also orally bioavailable and has treated pneumonia due to Pasteurella and Actinobacillus in pigs when incorporated into feed [300, 301]. 

The metabolism of alfentanil, a potent short-acting narcotic, is inhibited by macrolide antibiotics, resnlting in significant changes in half-life and clearance (86). 

Significant increases in serum carbamazepine concentrations due to reduced clearance (97) and prolonged half-life (98,122,123) can result in confusion, somnolence, ataxia, vertigo, nausea, and vomiting in patients taking macrolides (100,124,125). Toxicity can occur rapidly after addition of the macrolide and abate quickly on withdrawal (126). However, a retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interaction in patients who were also taking carbamazepine (127,128). 

The most frequently observed effects of macrolides on theophylline pharmacokinetics are increases in half-life and serum theophylline concentrations and reduced clearance (62). The interaction with theophylline is mainly seen with higher doses of macrolides and can result in theophylline toxicity (63). 

Indications Infections of the upper and lower respiratory tract, skin infections, sexually transmitted diseases Category Antibiotic, macrolide Half-life 68 hours... 

Indications Prophylaxis of organ rejection in renal transplants Category Antibiotic, macrolide Immunosupressant Non-calcineurin inhibitor Half-life 62 hours... 

Indications Various infections caused by susceptible organisms Category Antibiotic, macrolide Half-life N/A... 

Indications Ischemic heart disease, restenosis Category Angiogenesis inhibitor Macrolide immunosuppressant (Derivative of sirolimus) mTOR inhibitor Half-life 33 to 36 hours... 

Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella, J. A., Haskell, S. L., and Retsema, J. A. (1987). Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob. Agents Chemother. 31, 1948-1954. 

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