Pharmacokinetics of intravenous and oral midazolam in plasma and saliva in humans: usefulness of saliva as matrix for CYP3A phenotyping

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • Midazolam is a frequently used probe drug for CYP3A phenotyping in plasma. Midazolam and its hydroxy‐metabolites can be detected in saliva. WHAT THIS STUDY ADDS • The concentrations of midazolam and its hydroxy‐metabolites are much lower in saliva than in plasma, but the midazolam concentrations in both matrices show a significant linear correlation. • Saliva appears to be a suitable matrix for CYP3A phenotyping with midazolam, but very sensitive methods are required due to the low concentrations of midazolam and its hydroxy‐metabolites. AIMS To compare midazolam kinetics between plasma and saliva and to find out whether saliva is suitable for CYP3A phenotyping. METHODS This was a two way cross‐over study in eight subjects treated with 2 mg midazolam IV or 7.5 mg orally under basal conditions and after CYP3A induction with rifampicin. RESULTS Under basal conditions and IV administration, midazolam and 1′‐hydroxymidazolam (plasma, saliva), 4‐hydroxymidazolam and 1′‐hydroxymidazolam‐glucuronide (plasma) were detectable. After rifampicin, the AUC of midazolam [mean differences plasma 53.7 (95% CI 4.6, 102.9) and saliva 0.83 (95% CI 0.52, 1.14) ng ml −1 h] and 1′‐hydroxymidazolam [mean difference plasma 11.8 (95% CI 7.9 , 15.7) ng ml −1 h] had decreased significantly. There was a significant correlation between the midazolam concentrations in plasma and saliva (basal conditions: r = 0.864, P < 0.0001; after rifampicin: r = 0.842, P < 0.0001). After oral administration and basal conditions, midazolam, 1′‐hydroxymidazolam and 4‐hydroxymidazolam were detectable in plasma and saliva. After treatment with rifampicin, the AUC of midazolam [mean difference plasma 104.5 (95% CI 74.1, 134.9) ng ml −1 h] and 1′‐hydroxymidazolam [mean differences plasma 51.9 (95% CI 34.8, 69.1) and saliva 2.3 (95% CI 1.9, 2.7) ng ml −1 h] had decreased significantly. The parameters separating best between basal conditions and post‐rifampicin were: (1′‐hydroxymidazolam + 1′‐hydroxymidazolam‐glucuronide)/midazolam at 20–30 min (plasma) and the AUC of midazolam (saliva) after IV, and the AUC of midazolam (plasma) and of 1′‐hydroxymidazolam (plasma and saliva) after oral administration. CONCLUSIONS Saliva appears to be a suitable matrix for non‐invasive CYP3A phenotyping using midazolam as a probe drug, but sensitive analytical methods are required.