| First Author | Henderson CJ | Year | 2015 |
| Journal | Biochem J | Volume | 465 |
| Issue | 3 | Pages | 479-88 |
| PubMed ID | 25377919 | Mgi Jnum | J:218526 |
| Mgi Id | MGI:5617880 | Doi | 10.1042/BJ20140582 |
| Citation | Henderson CJ, et al. (2015) Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability. Biochem J 465(3):479-88 |
| abstractText | 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. |
