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Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors
N J Proctor1, G T Tucker, A Rostami-Hodjegan
1Molecular Pharmacology and Pharmacogenetics, Clinical Sciences Division (South), University of Sheffield, The Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|February 27, 2004
Summary
Recombinant human cytochromes P450 (rhCYPs) can predict drug clearance. New intersystem extrapolation factors (ISEFs) account for differences between rhCYPs and human liver enzymes, improving in vitro-in vivo extrapolation accuracy.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Biotechnology
Background:
- Recombinant human cytochromes P450 (rhCYPs) are underutilized for predicting human drug clearance (CL).
- Discrepancies in intrinsic activity between rhCYPs and human liver enzymes hinder accurate predictions.
- Systematic investigation of these discrepancies is needed.
Purpose of the Study:
- To define intersystem extrapolation factors (ISEFs) for improved in vitro-in vivo extrapolation of human drug CL using rhCYP data.
- To account for variance associated with interindividual variation in CYP abundance.
- To optimize experimental design for enhanced prediction accuracy.
Main Methods:
- Compiled a large database (n=451) of metabolic stability data.
- Derived ISEFs for common expression systems and CYP enzymes.
- Constructed statistical models for ISEFs to identify key covariates.
Main Results:
- Developed ISEFs to bridge the gap between rhCYP and human liver enzyme activity.
- Identified covariates influencing ISEFs, enabling optimization of experimental design.
- Demonstrated potential for increased accuracy in predicting human drug clearance.
Conclusions:
- rhCYP data, when adjusted by ISEFs, can reliably predict human drug clearance.
- ISEFs mitigate discrepancies in intrinsic activity and account for CYP abundance variations.
- Recommendations provided for future rhCYP studies to enhance drug clearance prediction.