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Correlation between the CYP3A‐mediated oral clearances of alprazolam, midazolam and triazolam
Author(s) -
Masica A. L.,
Mayo G.,
Wilkinson G. R.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.291
Subject(s) - triazolam , alprazolam , midazolam , cyp3a , pharmacology , clinical pharmacology , chemistry , oral administration , beagle , benzodiazepine , medicine , metabolism , cytochrome p450 , anxiety , psychiatry , receptor , sedation
Prediction of CYP3A‐mediated drug clearance from that of another drug has proven to be difficult. One possible explanation involves multiple sites within the catalytic pocket and, as consequence, subgrouping of enzyme‐drug interactions. In this case, intra‐subgroup relationships would likely be better than inter‐subgroup comparisons. Accordingly, the oral clearances of 3 benzodiazepines (alprazolam, midazolam, triazolam) with similar CYP3A‐mediated metabolism (1′‐ and 4‐hydroxylation), but different oral bioavailabilities were determined in 10 healthy subjects (7 men). Oral clearances of midazolam and triazolam were highly correlated (r s = 0.90, p <0.001); weaker relationships were present between alprazolam and triazolam (r s = 0.67, p = 0.03) and alprazolam and midazolam (r s = 0.59, p = 0.07). For midazolam and triazolam, which undergo significant first‐pass metabolism, oral clearance was highly determined by the estimated CYP3A‐mediated intestinal extraction ratio. Thus, even between closely related drugs, oral clearance is not readily predictable and appears to depend on the importance of first‐pass metabolism, especially in the intestine, and possibly regio‐specificity of the CYP3A‐mediated oxidation. Clinical Pharmacology & Therapeutics (2004) 75 , P77–P77; doi: 10.1016/j.clpt.2003.11.291