Azithromycin does not alter the effects of oral midazolam on human performance

Abstract

Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500 mg + 250 mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam. In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin+midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

“…Since some macrolides inhibit oxidative hepatic metabolism of various drugs, several studies have been conducted with the combination of AZM and midazolam [197–200]. A total of 64 healthy volunteers were included in a double-blinded randomized trial comparing the effect of co-administration of midazolam with AZM or ERY.…”

“…A total of 64 healthy volunteers were included in a double-blinded randomized trial comparing the effect of co-administration of midazolam with AZM or ERY. The authors concluded that ERY, and not AZM, enhanced the objective and subjective effects of midazolam via interference of AZM with the hepatic CYP3A metabolism of midazolam [200]. A double-blind 2-phase cross-over study of 10 healthy volunteers contradicts these findings, as no changes in PD or PK of midazolam were found except for a decrease in C max by 44% and a delay in t max from 1.0 to 1.25 hours [199].…”

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

“…More modest changes (two-to fourfold) were found following a single dose of grapefruit juice (181) and a period of erythromycin (161), clarithromycin (227), roxithromycin (228), fluconazole (144), or diltiazem (131) administration. By contrast, several days pretreatment with azithromycin (229)(230)(231) and terbinafine (226) had no effect on midazolam's metabolism. Thus, at the present time, measurement of changes in midazolam's clearance and the fractional clearance associated with the 1 -hydroxy pathway of metabolism after oral drug administration probably provides the best means by which quantitative alterations in intestinal and/or hepatic CYP3A resulting from a drug interaction activity can be determined in vivo.…”

“…This is especially the case when inhibition of metabolism occurs, since this often results in increased sedative effects. Thus, azole antifungal agents, some but not all macrolides, selective serotonin reuptake inhibitors, and calcium-channel antagonists such as verapamil and diltiazem have been shown to markedly enhance plasma levels of midazolam (131,139,144,161,200,(226)(227)(228)(229)(230)(231), triazolam (132,(265)(266)(267)(268), and alprazolam (268)(269)(270)(271)(272). Moreover, central nervous effects were increased and their duration prolonged.…”

Pharmacokinetic and Pharmacodynamic Consequences of Metabolism‐Based Drug Interactions with Alprazolam, Midazolam, and Triazolam

“…MDZ was found to have less interaction with roxythromycin 55,56 and no interaction with azithromycin. 51, 57 Effects of nefazodone, fluoxetine, and fluvoxamine on the pharmacokinetics of a single oral 10 mg dose of MDZ were investigated together in a randomized parallel study that used ketoconazole as a positive control. 58 Fluoxetine (60 mg/day for 5 days, then 20 mg/day for 6 days) and fluvoxamine (titrated to 200 mg/day) had no significant effect on MDZ, while nefazodone (titrated to 400 mg/day) and ketoconazole (200 mg/day for 11 days) increased AUC of MDZ to 4.8-fold and 11.7-fold of the baseline values, respectively.…”