INFLUENCE OF THE ANTIBIOTICS ERYTHROMYCIN AND AZITHROMYCIN ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF MIDAZOLAM

The pharmacokinetic and pharmacodynamic interaction between azithromyc in (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-7 0-8), a short-acting hypnotic agent, was investigated in an open, thre e-way cross-over study, including erythromycin (CAS 114-07-8) as a pos itive control. Twelve healthy male and female subjects had standard do ses 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 psych ometric tests performed. Erythromycin pretreatment (E) significantly c hanged the pharmacokinetics of midazolam compared to control (C), wher eas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h . ng . ml(-1) vs. (E) 662.7 h . ng ml(-1) (+) and (A) 220.0 h . ng . ml(-1); concentration maxima (C) 67.2 ng . ml(-1) vs. (E) 182.3 ng . m l(-1 +) and (A) 86.7 ng . ml(-1); elimination half-life (C) 2.21 h vs . (E) 4.85 h () and (A) 2.41 h ((*)p < 0.05 vs. (C), + p < 0.05 vs (A )). Pharmacodynamic tests (digit symbol substitution test; critical fl icker fusion test; subjective analog scale for rating of alertness; du ration of sleep) consistently showed significant differences after ery thromycin pretratment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant cha nges in the pharmacokinetics and pharmacodynamics of midazolam.