A potentially hazardous interaction between erythromycin and midazolam

Olkkola, Klaus T.; Aranko, Kari; Luurila, Harri; Hiller, Arja; Saarnivaara, L.; Himberg, Jaakko‐Juhani; Neuvonen, Pertti J.

doi:10.1038/clpt.1993.25

Cited by 288 publications

(80 citation statements)

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“…In vitro data indicate that midazolam metabolism is inhibited by many other drugs (Gascon and Dayer 1991). We have previously shown that erythromycin distinctly alters the pharmacokinetics of midazolain and potentiates the psychomotor actions of midazolain hazardously (Olkkola et al 1993). Now, using the same study design, the effect of roxithromycin on the pharmacokinetics of midazolam proved to be clearly smaller than the effect of erythromycin and appeared less likely to lead to clinically significant changes in the pharmacodynamics of midazolam.…”

Section: Discussionmentioning

confidence: 84%

“…The macrolide antibiotic erythromycin inhibits the metabolism of midazolam in vitro and also in humans (Byatt et al 1984;Gascon and Dayer 1991;Hiller et al 1990). In a previous study erythromycin treatment increased the area under the midazolam concentration-time curve more than four-fold and peak midazolam concentration almost three-fold after a 15-mg oral dose of midazolam, which caused more proPresented in part at the 18 th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 1993 Correspondence to: J. T. Backman, Department of Clinical Pharmacology, University of Helsinki, Paasikivenkatu 4, SF-00250 Helsinki, Finland found and prolonged psychomotor effects (Olkkola et al 1993).…”

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confidence: 99%

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A pharmacokinetic interaction between roxithromycin and midazolam

Backman

Aranko

Himberg

et al. 1994

Eur J Clin Pharmacol

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The interaction between roxithromycin and midazolam was investigated in a double-blind, randomised crossover study of two phases. Ten healthy volunteers were given roxithromycin (300 mg) or placebo once daily for 6 days. On the sixth day they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h. Roxithromycin administration significantly increased the area under the plasma midazolam concentration-time curve from 8.3 to 12.2 micrograms.ml-1.min and the elimination half-lives from 1.7 to 2.2 h. In psychomotor performance only minor differences were seen between the treatments in one of the measured psychomotor parameters. Thus, in contrast to the strong interaction between erythromycin and midazolam, the interaction between roxithromycin and midazolam appears less likely to be clinically significant.

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

A pharmacokinetic interaction between roxithromycin and midazolam

Backman

Aranko

Himberg

et al. 1994

Eur J Clin Pharmacol

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“…The latter is a second reaction, which has been proposed as a measure of the in vivo function of CYP3A4 (7). The ability of macrolide antibiotics, such as erythromycin, to influence the pharmacokinetics of other drugs is exemplified by the recent report (33) of the "undesirably severe and excessively longlasting hypnotic effects" seen when young adults were pretreated with erythromycin prior to oral administration of the 1,4-benzodiazepine short-acting hypnotic agent midazolam. Midazolam is metabolized by P450 3A4 (34).…”

Section: Discussionmentioning

confidence: 99%

Human cytochrome P450 3A4: enzymatic properties of a purified recombinant fusion protein containing NADPH-P450 reductase.

Shet

Fisher

Holmans

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

113

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Human cytochrome P450 3A4is recognized as the catalyst for the oxygen-dependent metaboism of a diverse group of medicafly important chemicals, inWuding the immunosuppressive agent cyclosporin; macrolide antibiotics, such as erythromycin; drugs such as benzphetamine, nifedipine, and cocaine; and steroids, such as cortisol and testosterone to name but a few. We have engineered the cDNA for human cytochrome P450 3A4 by linkage to the cDNA for the rat or human flavoprotein, NADPH-P450 reductase (NADPH:ferrihemoprotein oxidoreductase, EC 1.6.2.4). An enzymaticafly active fusion protein (rF450[mHum3A4/mRatOR]Ll) has been expressed at high levels in Escherichia coli and purified to homogeneity.Enzymatic studies show a requirement for lipid, detergent, and cytochrome bs for the 63-hydroxylation of steroids and the N-oxidation of nifedipine. In contrast, these additions are not required for the N-demethylation of erythromycin or benzphetamine. A spectrophotometricafly detectable metabolite complex of P450 3A4 is formed during the metabolism of triacetyloleandomycin, and this has a pronounced inhibitory effect on the metabolim of both testosterone and erthromycin. These resuits relate to the interpretation of current methods used to assess the in vivo activity of P450 3A4.One ofthe most versatile ofthe cytochrome P450s is the form present in human liver called CYP3A4, which catalyzes the oxidative metabolism of a wide array of different chemicals with markedly different structural characteristics (1). Interest has centered on this P450 since it is reported to be one of the more abundant P450s in human liver (2); it is inducible by a variety of agents including glucocorticoids as well as phenobarbital (3); it appears to play a central role in the metabolism of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin (4); it also catalyzes the 63-hydroxylation of a number of steroids including testosterone, progesterone, and cortisol (5). Clinical interest relates to the measurement of erythromycin metabolism by a breath test (6) and the presence of6f-hydroxylated steroids in urine (7) as indicators of CYP3A4 function for evaluation of transplant recipients.P450s ofthe 3A family were first characterized by Guzelian and colleagues (8) based on the ability ofthe catabolic steroid pregnenolone-16a-carbonitrile to induce a unique form of P450 (which they called P-450p). They also recognized the ability of the macrolide antibiotic triacetyloleandomycin (TAO) to serve as a powerful inducer of this type of P450-a result of interest because of the known ability of TAO and other compounds to form stable, metabolite-inhibitor complexes with P450 (9). Reconstitution studies using purified P450s of the 3A family have shown the need to include phospholipids, detergents, and cytochrome b5 when testing enzymatic activities (10, 11).

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“…Erythromycin administed orally for one week [7] inhibited the hepatic metabolism of midazolam, leading to an increase in its plasma concentrations and enhancement of its effects. Even single oral doses of erythromycin 750 mg have increased the plasma level of midazolam and enhanced its effects on human psychomotor performance [8].…”

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confidence: 99%

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

Mattila

Vanakoski

Idänpään-Heikkilä

1994

Eur J Clin Pharmacol

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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)

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A potentially hazardous interaction between erythromycin and midazolam

Cited by 288 publications

References 0 publications

A pharmacokinetic interaction between roxithromycin and midazolam

A pharmacokinetic interaction between roxithromycin and midazolam

Human cytochrome P450 3A4: enzymatic properties of a purified recombinant fusion protein containing NADPH-P450 reductase.

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

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