Pharmacokinetics macrolides

Pharmacokinetic/pharmacodynamic modeling indicates that the AUC/MIC ratio is predictive of outcome for this antibacterial suggesting that telithromycin is suitable for short-duration therapy and a once-daily dosing regimen even against / -lactam and macrolide-resistant pathogens... 

Pharmacology Telithromycin belongs to the ketolide class of antibacterials and is structurally related to the macrolide family of antibiotics. Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 508 ribosomal subunit. Pharmacokinetics ... 

Pharmacology Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. The mechanism of action of tacrolimus in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. Pharmacokinetics ... 

The macrolide antibacterials (including erythromycin, clarithromycin and telithromycin) are often implicated in interactions, most frequently as a result of inhibition of the CYP3A4 enzyme system in the liver and enterocytes. Erythromycin inhibits the metabolism of carbamazepine, ciclosporin and theophylline significant increases in serum levels and features of toxicity have been documented. Careful clinical and pharmacokinetic monitoring are required in a patient taking any of these drugs who requires concomitant erythromycin. 

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. 

Semisynthetic Derivatives. 3 -O-Acyl derivatives have not been found via fermentation, but chemical acylation of the 3/ -hydroxyl group yields products having good antibiotic activity and better pharmacokinetics than the parent macrolides. Two such compounds have been developed 3r/-O-propionyl-leucomycin Af (rokitamycin) C42H 9N015, formerly TMS-19-Q, and 9,3 -di-O-acetylmidecamyein (miokamycin) C HtiNOi . At least part of the in viva improvement was attributed to slower elimination of active metabolites from serum. 

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. 

Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmacokinet 1985 10 63-79. 

Honig PK, Wortham DC, Zamani K, et al. Comparison of the effect of macrolide antibiotics erythromycin, clarithromycin and azithromycin on terfenadine steady-state pharmacokinetics and electrocardiographic parameters. Drug Invest 1994 7 148-156. 

The improved in vitro spectrum, in vivo efficacy, and pharmacokinetics of certain esters of leucomycin-related macrolides logically led to the synthesis of analogous esters of tylosin. 3- and 4"-0-acyl derivatives were initially prepared by bioconversions with Streptomyces thermotolerans, a producer of carbomycin [76], From this small group, 3-0-acetyl-4"-0-isovalerylty-losin (AlV-tylosin) (14) Figure 5.6) was chosen for further study because of its activity against some tylosin-resistant organisms and its improved oral therapeutic and pharmacokinetic effects [61, 77], AlV-tylosin has now been commercially developed as a new veterinary antibiotic. 

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],... 

For some decades erythromycin was the only macrolide antibiotic available, but with the development of new macrolides with remarkable pharmacokinetic and safety features (1), it has met fierce competition and has, at least in some health-care systems, lost its place as the most important macrolide. 

Erythromycin can cause acute carbamazepine intoxication, probably by inhibiting its hepatic metabolism (63). Erythromycin may also directly inhibit the conversion of carbamazepine to its epoxide. In a controlled study of the effects of eiythromycin on carbamazepine pharmacokinetics in healthy volunteers, the clearance of a single dose of carbamazepine was reduced by 19% during erythromycin treatment (64). In contrast, the single-dose pharmacokinetics of phenytoin were not affected by erythromycin (65,66). After withdrawal of the macrolide, carbamazepine concentrations quickly return to normal (67). If co-administration of erythromycin and carbamazepine cannot be avoided, a dosage reduction of... 

Everolimus is an immunosuppressive macrolide that also has synergistic actions with ciclosporin and interrupts the proliferative responses of vascular and bronchial smooth muscle cells. In a phase I trial, its safety profile and pharmacokinetics were assessed during a 4-week course of once-daUy sequential ascending doses (0.75, 2.5, or... 

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 pharmacokinetics of ciclosporin can be altered by macrolides. Commonly observed changes include increases... 

The most frequent effects of macrohdes on theophylline pharmacokinetics are increased half-hfe and serum theophylline concentration and reduced clearance (133). The interaction with theophylline is mainly seen with higher doses of macrolides and can result in theophylhne toxicity (108). 

Periti P, Mazzei T, Mini E, Novell A. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet 1992 23(2) 106-31. 

Among the many antibiotics isolated from the actinomycetes isthe group of chemically related compounds called the mac-mlides. In I9S0, picromycin, the first of this group to be identified as a macrolide compound, was first reported. In 1952. erythromycin and carbomycin were reported us new antibiotics, and they were followed in subsequent years by other macrolides. Currently, more than 40 such compounds ate known, and new ones are likely to appear in the future. Of all of these, only two, erythromycin and oleandomycin, have been available consistently for medical use in the United States. In recent years, interest has shifted away from novel macrolides isolated from soil samples (e.g.,. spiramycin, josamycin, and rosamicin), all of which thus far have proved to be clinically inferior to erythromycin and semisynthetic derivatives of erythromycin (e.g., clarithromycin and azithromycin), which have superior pharmacokinetic properties due to their enhanced acid stability and improved distribution properties. 

Claforan cefotaxime, clarithromycin [ban, inn, usan] (Blaxln Klaricid ) is the 6-0-methyl derivative of erythromycin, a macrolide, and has superior pharmacokinetic properties. It can be used clinically as an oral or parenteral antibacterial to treat a wide variety of infections, including skin, soft tissue and respiratory tract infections. It is usually given to patients who are allergic to penicillin. 

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