Pharmacokinetics clarithromycin

Nelfinavir approximately doubles the sierum levels of azithromycin, but the ciinical significance of this is uncertain. Single doses of azithromycin have no effect on the levels of indinavir and nelfinavir. Ritonavir and atazanavir increase clarithromycin leveis. Amprenavir, indinavir and saquinavir do not have a clinically significant effect on clarithromycin pharmacokinetics. Clarithromycin has no important effect on the pharmacokinetics of amprenavir, atazanavir, darunavir, indinavir or ritonavir, but it increases tipranavir levels. Although both clarithromycin and erythromycin markedly raise saquinavir levels, this is not considered clinically important for short courses of these antibacteriais. 

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. 

In this example, clarithromycin, a potent CYP3A inhibitor blocks the principal pathway of pimozide metabolism (CYP3A), and plasma concentrations of pimozide increase. A higher pimozide concentration (a pharmacokinetic effect) is associated with prolongation of QT c in EKG readings and potentially fatal torsades de pointes (via potassium channel blockade, a pharmacodynamic effect see Flockhart et al., 2000, May-hew et ah, 2000). As exemplified by this vignette, the... 

Desta, Z., Kerbusch, T, and Flockhart, D.A. (1999) Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 65 10-20. 

Cheng KL, Nafziger AN, Peloquin CA, Amsden GW. Effect of grapefruit juice on clarithromycin pharmacokinetics. Antimicrob Agents Chemother 1998 42(4) 927-929. 

Ouellet D, Hsu A, Granneman G, et al. Pharmacokinetic interaction between ritonavir and clarithromycin. Clin Pharmacol Ther 1998 64 355-362. 

Triazolam plasma concentrations were determined by gas chromatography with electron capture detection (73,95). The pharmacokinetic results demonstrated that mean clearance during Trials B and C were nearly identical (413 and 416 mL/min, respectively) that is, coadministration of azithromycin had no effect on the pharmacokinetics of triazolam (Fig. 5). However, triazolam clearance was significantly reduced to 146 mL/min by erythromycin (Trial D) and to 95 mL/min by clarithromycin (Trial E). Thus, the in vivo kinetic results are highly consistent with the in vitro data. 

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. 

In an open, randomized, crossover, pharmacokinetic and pharmacodynamic study in 12 healthy volunteers who took clarithromycin 250 mg bd for 5 days, azithromycin 500 mg/day for 3 days, or no pretreatment, followed by a single dose of midazolam (15 mg), clarithromycin increased the AUC of midazolam by over 3.5 times and the mean duration of sleep from 135 to 281 minutes (69). In contrast, there was no change with azithromycin, suggesting that it is much safer for co-administration with midazolam. 

In a randomized, double-bhnd, pharmacokinetic-pharmacodynamic study, 12 volunteers took placebo or triazolam 0.125 mg orally, together with placebo, azithromycin, erythromycin, or clarithromycin. The apparent oral clearance of triazolam was significantly reduced by erythromycin and clarithromycin. The peak plasma concentration was correspondingly increased, and the half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced by erythromycin and clarithromycin (23). 

Azuma T, Ito S, Suto H, et al. (2000) Pharmacokinetics of clarithromycin in Helicobacter pylori eradication therapy in patients with liver cirrhosis. Aliment Pharmacol Ther 14 (Suppl 1) 216-222. 

A pharmacokinetic study has shown a minor interaction of amprenavir with clarithromycin in healthy men (8). 

Tsutsumi K, Kotegawa T, Kuranari M, Otani Y, Morimoto T, Matsuki S, Nakano S. The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers. J Clin Pharmacol 2002 42(10) 1159-64. 

Clarithromycin reduced the peak concentration and AUC of zidovudine at steady state by about 12% (32), possibly as a result of reduced zidovudine absorption (62). However, if the two drugs were taken at least 2 hours apart, the pharmacokinetics of zidovudine were unaffected. 

The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabu-tin have been studied in ten HIV-infected patients who were given rifabutin 300 mg qds in addition to fluconazole 200 mg qds and clarithromycin 500 mg qds (73). There was a 76% increase in the plasma AUC of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together. The authors concluded that patients should be monitored for adverse effects of rifabutin when it is co-administered with fluconazole or clarithromycin. 

Polis M, Haneiwich S, Kovacs J, et al. Dose escalation study to determine the safety, maximally tolerated dose and pharmacokinetics of clarithromycin with zidovudine in HIV-infected patients. In Interscience Conference on Antimicrobial Agents and Chemotherapy American Society for Microbiology, 1991. 

Peters DH, Clissold SP. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential. Drugs 1992 44(l) 117-64. 

Gillum JG, Brtrzzese VL, Israel DS, Kaplowitz LG, Polk RE. Effect of clarithromycin on the pharmacokinetics of 2, 3 -dideoxyinosine in patients who are seropositive for human immtmodeficiency virtrs. CUn Infect Dis 1996 22(4) 716-18. 

Jordan MK, Polis MA, Kelly G, Narang PK, Masur H, Piscitelli SC. Effects of fluconazole and clarithromycin on rifabutin and 25-O-desacetyhifabutin pharmacokinetics. Antimicrob Agents Chemother 2000 44(8) 2170-2. 

Ruf F, Chu S, Senders R, Sennello L. Effect of multiple doses of clarithromycin on the pharmacokinetics of theophylline. In International Conference on Antimicrobial Agents and Chemotherapy. Atlanta, Georgia, USA American Society for Microbiology, 1990. 

The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabutin... 

The effects of clarithromycin (250 mg bd) and itraconazole (200 mg od) for 4 days on the pharmacokinetics of ropivacaine (given intravenously as a single dose of 0.6 mg/kg on day 4) have been studied in a double-blind, three-way, crossover study in eight healthy volunteers (108). There were no significant changes in the... 

Jokinen MJ, Ahonen J, Neuvonen PJ, Olkkola KT. Effect of clarithromycin and itraconazole on the pharmacokinetics of ropivacaine. Pharmacol Toxicol 2001 88(4) 187-91. 

Edlund C, Alvan G, Barkholt L, Vacheron F, Nord CE. Pharmacokinetics and comparative effects of telithromycin (HMR 3647) and clarithromycin on the oropharyngeal and intestinal microflora. J Antimicrob Chemother 2000 46(5) 741-9. 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrohdes, especially clarithromycin (87-89,116), typically resnlting in prolongation of the QT interval and cardiac dysrhjdhmias (torsade de pointes) (111). The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine pins placebo (90). However, azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QTc interval. 

Qarithromycin (500 mg bd for 10 days) significantly increased the steady-state maximum plasma concentration and the steady-state AUC of loratadine (10 mg/day for 10 days) (92). In contrast, the addition of loratadine did not affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxyclarithromycin. No QTc interval exceeded 439 ms in any subject. 

Pharmacokinetic interactions with clarithromycin, erythromycin, and troleandomycin have been reviewed... 

Although zafirlukast inhibits CYP3A, it did not have any significant pharmacokinetic effect on single doses of azithromycin or clarithromycin in 12 healthy volunteers (190). 

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