Description

In vivo preclinical studies seek to demonstrate the efficacy of potential drugs and characterise their bioavailability, toxicity and metabolism. One of the key factors in determining the bioavailability and toxicity of a drug is metabolism by the liver associated cytochrome enzymes. As such, models in which specific metabolism associated cytochrome enzymes are selectively deleted provide key tools for preclinical drug development. 

Cytochrome b5 is an electron transfer component in a number of oxidative reactions in biological tissues. These include anabolic metabolism of fats and steroids as well as catabolism of xenobiotics and compounds of endogenous metabolism. Cytochrome b5 has been shown to be an electron transport hemoprotein for cytochrome P450 and therefore plays an important role in P450 associated drug metabolism.

The inventors have developed a mouse model in which cytochrome b5 has been deleted in the liver (Hepatic cytochrome b5 Null (HBN) mouse). The loss of hepatic cytochrome b5 results in a significant reduction of drug metabolism. Metabolism of all cytochrome P450 probe drugs tested (chlorozoxane, metroprolol, midazolam, tolbutamide and phenacetin) was significantly reduced (30-80% reduction). Circulating levels of the drugs post intravenous delivery were consistently increased and their clearance was consistently decreased in HBN mice compared to wild-type mice.

Application

Mouse models in which key metabolism enzymes are deleted can provide valuable models for assessing drug metabolism and toxicity at early stage in the drug development process. In addition, valuable information can be obtained on the tested compound relating to its contribution to efficacy and toxicity versus its metabolites.

This mouse model also represents a key tool for studying cytochrome b5 mediated metabolism in in vivo preclinical drug development. Liver cells extracted from the mouse (hepatic microsomes) can also be used to test new drugs in vitro.

Download the PDF of Cytochrome b5 KO mouse model for study of drug metabolism

For more information please contact

Dr George Tzircotis

+44 (0) 20 3469 6300 .(JavaScript must be enabled to view this email address)