Inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 by human liver microsomes

Dong Il Lee, Tae Ho Lee, Kyoung Ah Kim, Soon Ok Byun, Ji-Young Park

Research output: Contribution to journalArticle

Abstract

Background & Objectives : Macrolide antibiotics have been reported to cause several drug interactions with co-administered drugs clinically. However, there is no clear demonstration to reveal the relative potential to cause drug interaction. Therefore we investigated and compared the inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 (CYP3A4)-catalyzed reactions using human liver microsomes. Methods : Macrolide antibiotics including azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin was co-incubated with midazolam or testosterone, probe substrates of CYP3A4, in human liver microsomes, respectively. Metabolic activities of midazolam 1-hydroxylation and testosterone 6β-hydroxylation were determined using high-performance liquid chromatography and inhibitory effects of macrolide antibiotics were determined by the calculation of IC50 (the concentration of inhibitor representing 50% inhibitory potency) values by nonlinear regression method. Results : Among macrolide antibiotics tested, troleandomycin inhibited midazolam 1-hydroxylation and testosterone 6β-hydroxylation potently with IC 50 values of 52.3 and 65.9 μM, respectively. Clarithromycin and erythromycin showed moderate and similar inhibitory potency on both CYP3A4-catalyzed reactions. However, azithromycin and dirithromycin showed little inhibitory effects on CYP3A4-catalyzed midazolam 1-hydroxylation and testosterone 6β-hydroxylation. Conclusions : Dirithromycin and azithromycin showed little inhibitory effects on CYP3A4-catalyzed reactions. However, other macrolide antibiotics including troleandomycin, clarithromycin, and erythromycin caused significant inhibitory effects, thereby it should be cautious to co-medicated these drugs with other CYP3A4 substrates that have a narrow therapeutic range or concentration-dependent toxicity.

Original languageEnglish
Pages (from-to)129-137
Number of pages9
JournalJournal of Korean Society for Clinical Pharmacology and Therapeutics
Volume12
Issue number2
Publication statusPublished - 2004 Dec 1
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
dirithromycin
Macrolides
Liver Microsomes
Hydroxylation
Midazolam
Troleandomycin
Anti-Bacterial Agents
Azithromycin
Clarithromycin
Erythromycin
Drug Interactions
Pharmaceutical Preparations
Inhibitory Concentration 50
Testosterone
High Pressure Liquid Chromatography
1-testosterone

Keywords

  • Azithromycin
  • Clarithromycin
  • Cytochrome P450 3A4 (CYP3A4)
  • Dirithromycin
  • Drug interactions
  • Erythromycin
  • Macrolide antibiotics
  • Troleandomycin

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 by human liver microsomes. / Lee, Dong Il; Lee, Tae Ho; Kim, Kyoung Ah; Byun, Soon Ok; Park, Ji-Young.

In: Journal of Korean Society for Clinical Pharmacology and Therapeutics, Vol. 12, No. 2, 01.12.2004, p. 129-137.

Research output: Contribution to journalArticle

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abstract = "Background & Objectives : Macrolide antibiotics have been reported to cause several drug interactions with co-administered drugs clinically. However, there is no clear demonstration to reveal the relative potential to cause drug interaction. Therefore we investigated and compared the inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 (CYP3A4)-catalyzed reactions using human liver microsomes. Methods : Macrolide antibiotics including azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin was co-incubated with midazolam or testosterone, probe substrates of CYP3A4, in human liver microsomes, respectively. Metabolic activities of midazolam 1-hydroxylation and testosterone 6β-hydroxylation were determined using high-performance liquid chromatography and inhibitory effects of macrolide antibiotics were determined by the calculation of IC50 (the concentration of inhibitor representing 50{\%} inhibitory potency) values by nonlinear regression method. Results : Among macrolide antibiotics tested, troleandomycin inhibited midazolam 1-hydroxylation and testosterone 6β-hydroxylation potently with IC 50 values of 52.3 and 65.9 μM, respectively. Clarithromycin and erythromycin showed moderate and similar inhibitory potency on both CYP3A4-catalyzed reactions. However, azithromycin and dirithromycin showed little inhibitory effects on CYP3A4-catalyzed midazolam 1-hydroxylation and testosterone 6β-hydroxylation. Conclusions : Dirithromycin and azithromycin showed little inhibitory effects on CYP3A4-catalyzed reactions. However, other macrolide antibiotics including troleandomycin, clarithromycin, and erythromycin caused significant inhibitory effects, thereby it should be cautious to co-medicated these drugs with other CYP3A4 substrates that have a narrow therapeutic range or concentration-dependent toxicity.",
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AU - Kim, Kyoung Ah

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AU - Park, Ji-Young

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N2 - Background & Objectives : Macrolide antibiotics have been reported to cause several drug interactions with co-administered drugs clinically. However, there is no clear demonstration to reveal the relative potential to cause drug interaction. Therefore we investigated and compared the inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 (CYP3A4)-catalyzed reactions using human liver microsomes. Methods : Macrolide antibiotics including azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin was co-incubated with midazolam or testosterone, probe substrates of CYP3A4, in human liver microsomes, respectively. Metabolic activities of midazolam 1-hydroxylation and testosterone 6β-hydroxylation were determined using high-performance liquid chromatography and inhibitory effects of macrolide antibiotics were determined by the calculation of IC50 (the concentration of inhibitor representing 50% inhibitory potency) values by nonlinear regression method. Results : Among macrolide antibiotics tested, troleandomycin inhibited midazolam 1-hydroxylation and testosterone 6β-hydroxylation potently with IC 50 values of 52.3 and 65.9 μM, respectively. Clarithromycin and erythromycin showed moderate and similar inhibitory potency on both CYP3A4-catalyzed reactions. However, azithromycin and dirithromycin showed little inhibitory effects on CYP3A4-catalyzed midazolam 1-hydroxylation and testosterone 6β-hydroxylation. Conclusions : Dirithromycin and azithromycin showed little inhibitory effects on CYP3A4-catalyzed reactions. However, other macrolide antibiotics including troleandomycin, clarithromycin, and erythromycin caused significant inhibitory effects, thereby it should be cautious to co-medicated these drugs with other CYP3A4 substrates that have a narrow therapeutic range or concentration-dependent toxicity.

AB - Background & Objectives : Macrolide antibiotics have been reported to cause several drug interactions with co-administered drugs clinically. However, there is no clear demonstration to reveal the relative potential to cause drug interaction. Therefore we investigated and compared the inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 (CYP3A4)-catalyzed reactions using human liver microsomes. Methods : Macrolide antibiotics including azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin was co-incubated with midazolam or testosterone, probe substrates of CYP3A4, in human liver microsomes, respectively. Metabolic activities of midazolam 1-hydroxylation and testosterone 6β-hydroxylation were determined using high-performance liquid chromatography and inhibitory effects of macrolide antibiotics were determined by the calculation of IC50 (the concentration of inhibitor representing 50% inhibitory potency) values by nonlinear regression method. Results : Among macrolide antibiotics tested, troleandomycin inhibited midazolam 1-hydroxylation and testosterone 6β-hydroxylation potently with IC 50 values of 52.3 and 65.9 μM, respectively. Clarithromycin and erythromycin showed moderate and similar inhibitory potency on both CYP3A4-catalyzed reactions. However, azithromycin and dirithromycin showed little inhibitory effects on CYP3A4-catalyzed midazolam 1-hydroxylation and testosterone 6β-hydroxylation. Conclusions : Dirithromycin and azithromycin showed little inhibitory effects on CYP3A4-catalyzed reactions. However, other macrolide antibiotics including troleandomycin, clarithromycin, and erythromycin caused significant inhibitory effects, thereby it should be cautious to co-medicated these drugs with other CYP3A4 substrates that have a narrow therapeutic range or concentration-dependent toxicity.

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KW - Troleandomycin

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