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Drug Metabolism and Disposition Fast Forward
First published on February 5, 2009; DOI: 10.1124/dmd.108.024810

0090-9556/09/3705-1025-1034$20.00
DMD 37:1025-1034, 2009

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Evaluation of Recombinant Cytochrome P450 Enzymes as an in Vitro System for Metabolic Clearance PredictionsFormula

Rowan A. Stringer, Claire Strain-Damerell, Paul Nicklin, and J. Brian Houston

Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (R.A.S., C.S.-D., P.N.); and Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (J.B.H.)

The aim of this study was to explore the potential of recombinant cytochrome P450 (P450) enzymes for human metabolic clearance prediction. The relative abundance and relative activity approaches were compared as methods to bridge the gap between catalytic activities in recombinant P450 enzymes and human liver microsomes (HLMs). Relative activity factors were measured by determining the intrinsic clearance (CLint) of probe substrates (bufuralol-CYP2D6, diclofenac-CYP2C9, midazolam-CYP3A4, and phenacetin-CYP1A2) in recombinant P450s and 16 HLM donors. Simultaneous determination of drug depletion and metabolite formation profiles has enabled a direct comparison of these methods for CLint determination. Of the 110 drugs tested, 66% were metabolized by one or more P450 enzymes; of these 44% of were metabolized by CYP3A4 (0.3–21 µl/min/pmol of P450), 41% by CYP2D6 (0.6–60 µl/min/pmol of P450), 26% by CYP2C19 (0.4–8.1 µl/min/pmol of P450), 9% by CYP1A2 (0.4–2.5 µl/min/pmol of P450), and 4% by CYP2C9 (0.9–6.4 µl/min/pmol of P450). Recombinant enzymes demonstrated improved prediction reliability relative to HLMs and hepatocytes. The most reliable correlations in terms of lowest bias and highest precision were observed by comparing in vivo CLint, calculated using the parallel-tube model and incorporating fraction unbound in blood, with in vitro CLint determined using relative activity factors and adjusted for nonspecific binding. Predictions were less reliable using the relative abundance approach. For these drugs, recombinant P450 enzymes offer improved assay sensitivity compared with HLMs and cryopreserved hepatocytes for CLint determination using the drug depletion method.

Address correspondence to: Dr. Rowan A. Stringer, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK. E-mail: rowan.stringer{at}novartis.com






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