The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin

J. Christopher Gorski, David R. Jones, Barbara D. Haehner-Daniels, Mitchell A. Hamman, Edward M. O'Mara, Stephen D. Hall

Research output: Contribution to journalArticle

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Abstract

Objective: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. Methods: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. Results: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam availability were significantly increased from 0.31 ± 0.1 to 0.75 ± 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability was significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). Conclusion: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.

Original languageEnglish
Pages (from-to)133-143
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume64
Issue number2
DOIs
StatePublished - Aug 1998

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Cytochrome P-450 CYP3A
Clarithromycin
Midazolam
Liver
Oral Contraceptives
Isotopes
Gas Chromatography-Mass Spectrometry
Area Under Curve
Intestines
Oral Administration
Half-Life
Volunteers
Urine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Gorski, J. C., Jones, D. R., Haehner-Daniels, B. D., Hamman, M. A., O'Mara, E. M., & Hall, S. D. (1998). The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clinical Pharmacology and Therapeutics, 64(2), 133-143. https://doi.org/10.1016/S0009-9236(98)90146-1

The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. / Gorski, J. Christopher; Jones, David R.; Haehner-Daniels, Barbara D.; Hamman, Mitchell A.; O'Mara, Edward M.; Hall, Stephen D.

In: Clinical Pharmacology and Therapeutics, Vol. 64, No. 2, 08.1998, p. 133-143.

Research output: Contribution to journalArticle

Gorski, J. Christopher ; Jones, David R. ; Haehner-Daniels, Barbara D. ; Hamman, Mitchell A. ; O'Mara, Edward M. ; Hall, Stephen D. / The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. In: Clinical Pharmacology and Therapeutics. 1998 ; Vol. 64, No. 2. pp. 133-143.
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abstract = "Objective: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. Methods: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. Results: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam availability were significantly increased from 0.31 ± 0.1 to 0.75 ± 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability was significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). Conclusion: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.",
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AU - Jones, David R.

AU - Haehner-Daniels, Barbara D.

AU - Hamman, Mitchell A.

AU - O'Mara, Edward M.

AU - Hall, Stephen D.

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N2 - Objective: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. Methods: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. Results: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam availability were significantly increased from 0.31 ± 0.1 to 0.75 ± 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability was significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). Conclusion: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.

AB - Objective: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. Methods: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. Results: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam availability were significantly increased from 0.31 ± 0.1 to 0.75 ± 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability was significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). Conclusion: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.

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