Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability.
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.
*Division of Cancer Research, Level 9, Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, U.K.
Colin J
CJ
Henderson
*Division of Cancer Research, Level 9, Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, U.K.
Lesley A
LA
McLaughlin
†Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
Maria
M
Osuna-Cabello
†Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
Malcolm
M
Taylor
†Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
Ian
I
Gilbert
*Division of Cancer Research, Level 9, Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, U.K.
Aileen W
AW
McLaren
†Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
C Roland
CR
Wolf
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D005260:Female; D019426:Integrases / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008874:Midazolam / Q000378:metabolism* / Q000493:pharmacokinetics; D019888:Nelfinavir / Q000378:metabolism* / Q000493:pharmacokinetics; D017374:Paroxetine / Q000378:metabolism* / Q000493:pharmacokinetics
D017374:Paroxetine; C045073:Cre recombinase; D019426:Integrases; D019888:Nelfinavir; D008874:Midazolam