Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam
Zimmermann, T.; Yeates, R.A.; Laufen, H.; Scharpf, F.; Leitold, M.; Wildfeuer, A.
Arzneimittel-Forschung 46(2): 213-217
1996
ISSN/ISBN: 0004-4172 PMID: 8720318 Document Number: 1039
The pharmacokinetic and pharmacodynamic interaction between azithromycin (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-70-8), a short-acting hypnotic agent, was investigated in an open, three-way cross-over study, including erythromycin (CAS 114-07-8) as a positive control. Twelve healthy male and female subjects had standard doses of azithromycin (500 mg o.d. over 3 days), or erythromycin (500 mg t.i.d. over 5 days), or no pretreatment. On the day of the last dose, they ingested 15 mg midazolam. Blood samples were collected and psychometric tests performed. Erythromycin pretreatment (E) significantly changed the pharmacokinetics of midazolam compared to control (C), whereas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h cntdot ng cntdot ml-1 vs. (E) 662.7 h cntdot ng cntdot ml-1 *+ and (A) 220.0 h cntdot ng cntdot ml-1; concentration maxima (C) 67.2 ng cntdot ml-1 vs. (E) 182.3 ng cntdot ml-1 *+ and (A) 86.7 ng cntdot ml-1; elimination half-life (C) 2.21 h vs. (E) 4.85 h * and (A) 2.41 h (* p lt 0.05 vs. (C), + p lt 0.05 vs. (A)). Pharmacodynamic tests (digit symbol substitution test; critical flicker fusion test; subjective analog scale for rating of alertness; duration of sleep) consistently showed significant differences after erythromycin pretreatment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.
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