Comparison of the Effect of the Macrolide Antibiotics Erythromycin, Clarithromycin and Azithromycin on Terfenadine Steady-State Pharmacokinetics and Electrocardiographic Parameters

Honig, Peter K.; Wortham, Dale C.; Zamani, Kaveh; Cantilena, Louis R.

doi:10.1007/bf03258467

Cited by 85 publications

(27 citation statements)

References 17 publications

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“…For example, terfenadine's plasma levels, which are usually below the assay detection limit of 5 ng/ml, were measurable in some but not all subjects pretreated with erythromycin (113,191), and the interaction with ketoconazole resulted in 16-to 73-fold reduction in the antihistamines' oral clearance (192). Pronounced variability was also found in the interaction of grapefruit juice with various CYP3A substrates (119).…”

Section: Interindividual Variabilitymentioning

confidence: 92%

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Thummel

Wilkinson

1998

Annu. Rev. Pharmacol. Toxicol.

761

515

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Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.

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Section: Interindividual Variabilitymentioning

confidence: 92%

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Thummel

Wilkinson

1998

Annu. Rev. Pharmacol. Toxicol.

761

515

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“…Honig et al reported that after oral administration of a regular dose of macrolides to healthy volunteers, EM evoked 15 ms of Q-T interval prolongation on average, while CAM and AZM did not elicit obvious Q-T interval prolongation (13). Other studies reported the maximum effect of CAM for corrected Q-T interval prolongation in healthy volunteers as being 7 to 11 ms (4,28).…”

Section: Vol 44 2000 Q-t Interval Prolongation By Macrolides 2633mentioning

confidence: 99%

Comparative Pharmacodynamic Analysis of Q-T Interval Prolongation Induced by the Macrolides Clarithromycin, Roxithromycin, and Azithromycin in Rats

Ohtani

Taninaka

Hanada

et al. 2000

Antimicrob Agents Chemother

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In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms ⅐ ml/g for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.Macrolide antibiotics have been widely used for the treatment of infections caused by gram-positive organisms. Many macrolide antibiotics inhibit the metabolic activity of cytochrome P450 3A4 in the liver and intestine in an irreversible manner (8,22). With concomitant administration of macrolide antibiotics and potentially arrhythmogenic agents, such as terfenadine or astemizole, fatal ventricular arrhythmias, including torsades de pointes (TdP), were reported to occur as a result of an increase in the concentrations of the unchanged drugs in plasma (3,12). Besides the metabolic inhibition, erythromycin (EM) and clarithromycin (CAM) themselves possess arrhythmogenic activities and induce Q-T interval prolongation, resulting in ventricular arrhythmia, such as TdP (14,15,17,23). In isolated heart preparations from guinea pigs and dogs, EM was also shown to prolong the Q-T interval and action potential duration (1, 5). We have proved by a pharmacokineticpharmacodynamic analysis with rats that EM at its clinical range induces Q-T interval prolongation in a concentrationdependent manner (9). Taking these facts into consideration, extra care should be taken for erythromycin-treated patients with cardiographic risk factors.For making the choice of macrolide antibiotics, it is important to quantitatively estimate and compare the arrhythmogenic potencies of macrolide antibiotics. However, few studies have been conducted to quantitatively evaluate the arrhythmogenic...

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“…Like ketoconazole, erythromycin has been reported to cause severe cardiac toxicity with terfenadine when coadministered in humans (Food and Drug Administration, 1990). Honig et al (1994) have reported that the plasma concentrations of terfenadine, which is undetectable when given alone (60 mg b.i.d. for 7 days), increased to detectable levels following coadministration of erythromycin (500 mg t.i.d.…”

mentioning

confidence: 99%