Clarithromycin 14 -hydroxy

Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxy clarithromycin, 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. 

Metabolism Erythromycin is extensively metabolized and is known to inhibit the oxidation of a number of drugs through its interaction with the cytochrome P-450 system (see p. 14). Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity interference with the metabolism of drugs such as theophylline and carbamazepine has been reported. Azithromycin does not undergo metabolism. 

Garey KW, Peloquin CA, Godo PG, Nafziger AN, Amsden GW. Lack of effect of zafirlukast on the pharmacokinetics of azithromycin, clarithromycin, and 14-hydroxy-clarithromycin in healthy volunteers. Antimicrob Agents Chemother 1999 43(5) 1152-5. 

IS% of the 14-hydroxy metabolite is excreted in the urine. Biliary excretion of clarithromycin is much lower than that of erythromycin. Clarithromycin is widely distributed into the tissues, which retain much higher concentrations than the plasma. Protein-binding fractions in the plasma range from 65 to 70%. The plasma half-life of clarithromycin is 4.3 hours. 

The 6-O-methyl derivative has been added to this antibiotic group (Clarithromycin, Biaxin, 1991). The 14-hydroxy metabolite is also active. Its spectrum is not significantly superior to the parent drug (e.g., methicilin-resistant staph are also resistant). Dosing frequency is more convenient, however, and it appears to have fewer gastric side effects. 

Figure 118. Acid degradation of showing the stabilizing effect of substitution of a methoxy for a hydroxy group, erythromycin (a) and clarithromycin (b) at 37°C. (Reproduced from Ref. 508 with permission.)...

Goldman, R. C., Zakula, D., Hamm, R., Beyer, J., and Capobianco, J. (1994). Tight binding of clarithromycin, its 14-(/f)-hydroxy metabolite, and erythromycin to Helicobacter pylori ribosomes. Antimicrob. Agents Chemother. 38, 1496-1500. 

Clarithromycin (6-0-methylerythromycin) (see Fig. 7 in a later section) is synthesized by substituting a methoxy group for the C-6 hydroxy group of erythromycin [42]. This substitution creates a more acid-stable antimicrobial and prevents the degradation of the erythromycin base to the hemiketal intermediate. The increased acid stability of clarithromycin results in improved oral bioavailability and reduced gastrointestinal intolerance [43]. A 250-mg oral dose of clarithromycin resulted in a C ,ax of 0.7-0.8 mg/1, achieved at 2 hr in healthy subjects [44]. Double this parameter would be expected for a 500-mg dose. The bioavailability of clarithromycin, as indicated by the appearance of the parent compound in plasma, is 52-55% after administration of the dmg in tablet form [44]. In other cases, clarithromycin has oral bioavailability varying between 55% and 68% [3]. Concomitant ingestion of food increases its oral bioavailability by 25%... 

When single doses of 100, 200, 400, 600, 800, and 1200 mg of clarithromycin were compared in healthy subjects, the pharmacokinetics of the parent drug and metabolite were nonlinear [51], with apparent capacity-limited formation of the 14-(i )-hydroxy metabolite at doses of >600 mg. Nonlinear kinetics were also seen in studies of single and multiple doses of clarithromycin, where increases in C ,ax and AUC of the parent drug were more than proportionate with the dosages [52]. In another study, the AUC for clarithromycin increased 13-fold, with a 4.8-fold increase in dose. Pharmacokinetic data suggest that nonlinearity was due predominantly to a decrease in the apparent metabolic clearance, which fell from 913 to 289 ml/min (Table II) [50]. 

Clarithromycin undergoes extensive first-pass metabolism, with the of the active 14-(/ )-hydroxy metabolite in plasma being higher after oral rather than... 

Fig. 7. Metabolic pathway of clarithromycin in man. DM, A -desmethylclarithromycin DDM, A. A -didesmethylclarithromycin 14-0H(R), 14-hydroxy(i )-clarithromycin 14-OH(R)-DM, 14-hydroxy- R)-A -desmethylclarithromycin 14-0H(S), 14-hydroxy(5)-clarithromycin 14-OH(R)-Declad, 14-hydroxy-(/ )-descladinosylclarithromycin Declad, descladinosylclarithromycin 14-OH(S)-DM, 14-hydroxy(5)-A -demethylclarithromycin. (Reprinted with...

Both and AUC values for clarithromycin and 14-(/ )-hydroxy-clarithromycin increased markedly in patients with renal impairment after five consecutive 500-mg doses of the parent drug [73]. Creatinine clearance (CLcr) was significantly (p <... 

Potent inhibitors (/fi <1.0 pM) of CYP3A are likely to have a pronounced effect on the metabolism of clarithromycin. This is clinically relevant because 14-(/ )-hydroxy-clarithromycin is a pharmacologically active metabolite [72, 126]. In agreement, in patients receiving ritonavir, increased plasma concentrations of both ritonavir and clarithromycin and decreased 14-(/ )-hydroxy-clarithromycin (AUC ... 

Hardy, D. J., Swanson, R. N., Rode, R. A., Marsh, K., Shipkowitz, N. L., and Clement, J. J. (1990). Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus Influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans. Antimicrob. Agents Chemother. 34, 1407-1413. 

Dabemat, H., Delmas, C., Seguy, M., Fourtillan, J. B., Girault, J., and Lareng, M. B. (1991). The activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae, determined by in vitro and serum bactericidal tests. J. Antimicrob. Chemother. 27, 19-30. 

Delavirdine may increase the levels of clarithromycin, whereas efavirenz and nevirapine may reduce clarithromycin levels, and increase those of its hydroxy metabolite. Clarithromycin does not appear to affect the pharmacokinetics of delavirdine, efavirenz or nevirapine to a clinically relevant extent. There is no pharmacokinetic interaction between azithromycin and efavirenz. A case of a neuropsychiatric reaction has been attributed to the use of clarithromycin in a man taking nevirapine. 

The manufacturer notes that the concurrent use of clarithromycin 500 mg twice daily and efavirenz 400 mg daily for 7 days reduced the AUC of clarithromycin by 39% and increased the AUC of its hydroxy metabolite by 34%. Moreover, 46% of subjects receiving the combination developed a rash. Clarithromycin had minimal effect on the pharmacokinetics of efavirenz. ... 

The manufacturer notes that the AUC of nevirapine was increased by 26% by clarithromycin, when compared with historical controls. The AUC of clarithromycin was reduced by 31% and the AUC of its hydroxy metabolite was increased by 42%. - A man developed hyperactivity (poor concentration, anxiety, suicidal and homicidal ideation) when taking clarithromycin and antiretroviral drugs, including nevirapine. This was thought to be due to aceumulation of the hydroxy metabolite of clarithromycin. ... 

Tipranavir. The manufaeturer notes that tipranavir given with low-dose ritonavir increased the AUC and minimum levels of clarithromycin by 19% and 68%, respectively, and decreased the AUC ofthe 14-hydroxy active metabolite by over 95%. Clarithromycin more than doubled the minimum levels of tipranavir." ... 

The cyclic 11,12-carbonate of erythromycin represents a previously recognized method for stabilization of erythromycin by maintaining an equilibrium between the 6-hydroxy-9-keto and 6,9-hemiketal forms [44]. A new direction within this approach was recently reported with a series of cyclic 11,12-carbamate derivatives of erythromycin and clarithromycin (see Fig. 5), prepared by a general sequence of 10,11-dehydration, 12-0-carbamoylation, and intramolecular cyclization [45, 46]. Other structural modifications within this part of the erythromycin molecule include 10,11-anhydroerythromycin, previously synthesized from the cyclic 11,12-carbonate [47],... 

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