Demonstration of  in vivo efficacy using small amounts of compound.

The absence of drug metabolism in the liver can dramatically increase the potency of compounds in the HRN™ mouse, as it maximises the total exposure to small doses of compound. This capability can be used to determine the pharmacological response to low concentrations of compound that may otherwise have no observable effect. This is extremely useful in drug discovery when only small amounts of compound are available, or when compounds are normally subject to rapid phase 1 metabolism.

A dramatic example of this is shown below, which shows the response to pentobarbital in normal and HRN™ mice. In normal mice (green bars) pentobarbital induces anaesthesia, the extent of which is proportional to the administered dose. The duration of anaesthetic effect is dependent on metabolism of the pentobarbital, as the mice awake once they have metabolised the pentobarbital. The HRN™ mice never wake up as they are unable to metabolise and hence can never clear the anaesthetic (the experiment was deliberately stopped after 2 hours).  As a consequence, the HRN™ mice are also much more sensitive to the pharmacological effects as low concentrations that do not induce any effect in normal mice, are extremely potent in HRN™mice (eg 20mg/Kg).

Induction of anaesthesia by pentobarbital in normal and HRN mice Pentobarbital was administered by intraperitoneal injection to groups of wild type and HRN™ mice (n=3) at four concentrations, and the time taken to regain the righting reflex was measured. HRN™ mice fail to regain consciousness even at concentrations (20mg/Kg) that are ineffective in control mice.