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Received for publication June 8, 2004.
Revised August 31, 2004.
Accepted for publication August 31, 2004.
A systematic kinetic analysis of the metabolism of five benzodiazepines (low to high clearance compounds) was performed in CYP3A4, CYP3A5 and CYP2C19 baculovirus-expressed recombinant systems. The data obtained in the expression systems were scaled and compared to human liver microsomal predicted clearance and observed in vivo values, using either CYP relative activity factors (RAF) or the relative abundance approach. Inter-individual variability, both in content (CYP3A4, CYP3A5) and activity (CYP3A4, CYP3A5 and CYP2C19), were incorporated in the clearance prediction by bootstrap analysis. These re-sampling Monte Carlo based simulations were performed in order to justify any distribution assumptions in the generated range of the predicted clearance due to a limited sample size. Therefore, this approach allowed extrapolation of the recombinant clearance data to specific population groups and investigation of the role of 'minor' forms like CYP3A5 and CYP2C19 in comparison to the most prolific CYP3A4. The use of quinidine 3-hydroxylation and alprazolam 1'-hydroxylation, as RAF markers for CYP3A4 and CYP3A5 activity, respectively, and the incorporation of variability improved the clearance prediction of the selected benzodiazepines (apart from flunitrazepam) to within the 2-fold of the in vivo value. Clearance estimates from the immunoquantified protein levels was approximately 8-fold lower in comparison to the RAF approach. The differences observed in the benzodiazepines metabolite pathway ratios between CYP3A4 and CYP3A5, particularly for 1'- to 4-hydroxymidazolam and alprazolam provided useful measure of inter-individual differences within the CYP3A family.
Key words:
CYP3A, drug clearance, in vitro-in vivo prediction, Monte Carlo simulations, recombinant proteins
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