A study of the interaction between dirithromycin and astemizole in healthy adults.
The effect of a standard regimen of dirithromycin, a macrolide antibiotic, on the single-dose pharmacokinetics of the H (1) receptor blocker astemizole was evaluated in a sample of 18 healthy young adults (nine males and nine females). The study was conducted in a two-way cross-over fashion after the subjects had been randomly given either dirithromycin (two 250 mg tablets) or placebo (two tablets) every morning for 10 days. On the morning of the fourth dose of either dirithromycin or placebo each subject ingested a single 30-mg oral dose (three 10-mg tablets) of astemizole. The disposition kinetics of both astemizole and its major metabolite, N-desmethylastemizole, were characterized after measuring the concentrations of both analytes in the serum fraction of serial blood samples collected for 14 days after the astemizole dose. In addition, corrected QT (QT(c) ) intervals were estimated from electrocardiogram rhythm strips that were run 24 hours prior to the astemizole dose, 12 hours after the astemizole dose, and after the last treatment (dirithromycin or placebo) dose in both study periods. Pharmacokinetic parameters that were measured for both astemizole and N-desmethylastemizole during each treatment were: C(max), t(max), AUC (0-infinity), CL(oral), half-life, and volume of distribution (V). None of the parameters for N-desmethylastemizole was different when comparing data by ANOVA from the dirithromycin treatment period with that of the placebo treatment period. On the other hand, during dirithromycin treatment astemizole CL(oral) was 34% slower, volume of distribution was 24% larger, and half-life was 84% longer. Generally, all QT ( c ) intervals did not appear to be affected by dirithromycin treatment. The changes in astemizole kinetics could not be attributed to its N-demethylation since the dispositional kinetics of N-desmethylastemizole were unaffected by dirithromycin. Therefore, it is difficult to ascertain the clinical significance of the changes in astemizole kinetics. Since there were no significant differences for mean QT(c) intervals and no effect of dirithromycin treatment on N-desmethylastemizole kinetics, it is unlikely that a standard regimen of dirithromycin would place a patient taking astemizole at an increased risk of torsade de pointes or related ventricular arrhythmias.
Bachmann
K
K
Center for Applied Pharmacology, The University of Toledo College of Pharmacy, OH 43606, USA.
Sullivan
T J
TJ
Reese
J H
JH
Jauregui
L
L
Miller
K
K
Scott
M
M
Stotka
J
J
Harris
J
J
D000293:Adolescent; D000328:Adult; D018926:Anti-Allergic Agents / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D016589:Astemizole / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D018592:Cross-Over Studies; D004347:Drug Interactions; D004917:Erythromycin / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D018942:Macrolides; D008297:Male; D008875:Middle Aged
D018926:Anti-Allergic Agents; D000900:Anti-Bacterial Agents; D006634:Histamine H1 Antagonists; D018942:Macrolides; C053853:dirithromycin; D004917:Erythromycin; D016589:Astemizole; C040463:desmethylastemizole