Dissecting the contribution of the Cyp3a family to total bioavailability
The problem
The CYP3A family is responsible for the metabolism of more clinically-used drugs than any other. In humans, CYP3A4 catalyzes the metabolism of over 50% of drugs in clinical use[1]. Although in vitro studies can be used to determine if a compound in development is a CYP3A4 substrate, until now there has been no corresponding in vivo system to assess the impact of the CYP3A family on bioavailability, metabolism and toxicity.
The solution
In mice, at least six Cyp3a isoforms have been identified; Cyp3a11, Cyp3a13, Cyp3a16, Cyp3a25, Cyp3a41 and Cyp3a44. Of these, Cyp3a11 appears to contribute the most to xenobiotic metabolism. All Cyp3a genes (with the exception of 3a13, which does not appear to be constitutively expressed) have been removed in the transADMETTM Cyp3a (7-gene) Knockout, resulting in a model that can be used to dissect the impact of Cyp3a metabolism in an in vivo system, before entering the clinic.
Example study design
Example results
Pharmacokinetics for the test compound dexamethasone (DEX) was compared in the wild type and Cyp3a (7-gene) Knockout mice following 4 days of DEX treatment. Clear differences in DEX pharmacokinetics were observed in the different mouse lines, with an increase in maximal DEX serum concentrations in Cyp3a (7-gene) Knockout mice. These results demonstrate that CYP3A enzymes play an important role in the metabolism of DEX. The Cyp3a (7-gene) Knockout mice also demonstrated higher susceptibility to DEX-induced hepatotoxicity as a result of increased exposure to the parent compound.
Figure 1: Dexamethasone pharmacokinetics in WT and Cyp3a (7-gene) knockout mice. (A) Plasma concentration curve after 4 daily treatments with DEX at 30mg/kg I.P. (B) Total areas under the concentration/time curve (AUC) calculated from the DEX pharmacokinetics. Data are mean ± SD (n=3 for Cyp3a (7-gene) knockout mice; n=4 for wild type)
Cyp3a knockout mice can be used to demonstrate the impact of this enzyme family on metabolism and bioavailability, either in microsomes or in whole body PK studies, before entering the clinic.
Further data is available on request from CXR Biosciences.
Availability
CXR and Taconic have partnered to make the transADMETTM Cyp3a (7-gene) Knockout model commercially available.
Contract services: CXR are co-exclusive suppliers of contract research services using transADMETTM mice. We also offer consultancy and advice to our customers.
For more information on contract research services at CXR using the transADMETTM mice, contact us here or at transadmet@cxrbiosciences.com.
Off the shelf mice: Mice may be purchased directly from Taconic by both academic and for-profit customers. To purchase transADMETTM mice, please visit the relevant model webpages:
For questions regarding distribution of these models, please contact Dr. Megan MacBride.
[1] Guengerich FP. (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1-17.
The HRN™ mouse.
A unique mouse model with no hepatic CYP450 activity, that can be used to determine the effects of first-pass hepatic CYP 450 metabolism on the pharmacokinetics, efficacy and toxicity of compounds.
In vivo screening PK studies.
Small, cost effective PK studies, where multisampling techniques in mouse mean compound and animal use is minimised.
