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

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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 was significantly increased from 0.31 ± 0.1 to 0.75 +‐ 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were 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. Clinical Pharmacology & Therapeutics (1998) 64, 133–143; doi: