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01 Feb 2015

Colin J. Henderson*, Lesley A. McLaughlin*, Maria Osuna‑Cabello†, Malcolm Taylor†, Ian Gilbert†, Aileen W. McLaren* and C. Roland Wolf†1
*Division of Cancer Research, Level 9, Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, U.K., and †Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.

The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs-paroxetine, midazolam, nelfinavir-and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data.