Liver clarithromycin

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. 

Clarithromycin is readily and rapidly absorbed after oral administration and is metabolized significantly in liver. Active metabolite is excreted by kidney and other routes. 

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. 

Figure 3 Rates of formation of 4-OH-triazolam from triazolam (250 pM) by human liver microsomes in vitro. Each point is the mean ( SE) of four microsomal preparations. Reaction velocities when preparations were preincubated with the macrolide agents are expressed as a percentage of the control velocity with no inhibitor present (inhibitor = 0). Mean IC50 were TAO, 3.3 pM erythromycin, 27.3 pM clarithromycin, 25.2 pM azithromycin, >250 pM. Abbreviations IC50, 50% inhibitory concentrations TAO, troleandomycin. Source Adapted, in part, from Ref. 77.

Distribution Erythromycin distributes well to all body fluids except the cerebrospinal fluid (CSF). It is one of the few antibiotics that diffuses into prostatic fluid and has the unique characteristic of accumulating in macrophages. It concentrates in the liver. Inflammation allows for greater tissue penetration. Similarly, clarithromycin and azithromycin are widely distributed in tissues. Serum levels of azithromycin are low the drug is concentrated in neutrophils, macrophages, and fibroblasts. 

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. 

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. 

IMATINIB 1. ANTIBIOTICS - clarithromycin, erythromycin 2. ANTIFUNGALS -fluconazole, itraconazole, ketoconazole voriconazole 3. ANTIVIRALS -efavirenz, ritonavir 4. GRAPEFRUIT JUICE 5. H2 RECEPTOR BLOCKERS - cimetidine t imatinib levels with t risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy) Due to inhibition of CYP3A4-mediated metabolism of imatinib Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes and liver function, and for cardiotoxicity... 

As in the liver, drugs that undergo renal P-gp transport are susceptible to interactions resulting from modulation of P-gp- Inhibition of renal P-gp may lead to the development of unexpected toxicities or improved clinical efficacy secondary to increased drug exposure. Clarithromycin was found to increase the bioavailability of and reduce the renal clearance of digoxin in a group of healthy volunteers, resulting... 

Fox JC, Szyjkowski RS, Sanderson SO, Levine RA. Progressive cholestatic liver disease associated with clarithromycin treatment. J Clin Pharmacol 2002 42(6) 676-80. 

The MACH-2 study has assessed the role of omeprazole in triple therapy in 539 patients with duodenal ulcers associated with H. pylori (3). The addition of omeprazole resulted in significantly higher eradication rates (over 90%) than antibiotics alone (amoxicillin plus clarithromycin about 25% clarithromycin plus metronidazole 70%), and reduced the impact of primary resistance to metronidazole. About one-third of the patients who took amoxicillin reported diarrhea/loose stools. The frequency of taste disturbance was dose-dependent with clarithromycin. Increased liver enzymes were more commonly reported in those taking metronidazole. The addition of omeprazole did not increase the frequency of reported adverse effects. 

Erythromycin can cause two different types of liver damage (36,37), benign increases in serum transaminases, which may or may not recur on rechallenge, and cholestatic hepatitis. Reports of intrahepatic cholestasis with azithromycin (38), clarithromycin (39,40), and josamycin (41) suggest that the newer macrolides are not free of this adverse effect, although the relative risks compared with erythromycin are unclear. Similar involvement of the liver has been seen with the ester of triacetyloleandomycin, but not with the unesterified antibiotic. 

Fig. 6. Uptake of C-clarithromycin (O) and C-erythromycin ( ) by isolated lung (a) or liver (b) cells. Each value represents the mean S.E. of six experiments. P < 0.01 and P < 0.001 versus erythromycin. (From Kohno et al. [61], Fig. 2, p. 507.)...

Several lines of evidence in the in vitro study using human liver microsomes have demonstrated that member(s) of the CYP3A subfamily, most likely CYP3A4, are the principal human liver microsomal enzymes involved in the metabolism of clarithromycin [71]. 

As with erythromycin, drug interactions are extremely important with clarithromycin. Because clarithromycin inhibits the hepatic cytochrome P-450 system, it may result in increased levels of multiple medications metabolized by the liver [19]. Clarithromycin appeared to increase the mean steady-state plasma theophylline concentration and AUC from 15.6 p.g/ml and 249 pg hr/ml, respectively, in the absence of clarithromycin, to 18.4 pg/ml and 291 pg hr/ml in the presence of clarithromycin p< 0.001 for both concentration and AUC). Although a modest increase was seen in the plasma theophylline concentration, the concentration remained within the therapeutic range, and concurrent administration of clarithromycin and theophylline was safe and well tolerated [121]. Although the magnitude of elevation in theophylline was small, caution should be used when... 

Rodrigues, A. D., Roberts, E. M., Mulford, D. J., Yao, Y, and Quellet, D. (1997). Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P-450 3A (CYP3A) subfamily. Drug Metab. Dispos. 25, 623-630. 

Erythromycin and clarithromycin are metabolized by the liver and excreted through the bile... 

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