Centre for Drug Candidate Optimisation - Disciplines

Bioavailability and Pharmacokinetics

In vivo assessment

Pharmacokinetics characterises the absorption, distribution, metabolism and excretion (ADME) properties of a drug candidate, allowing identification of limiting features in relation to the desired route of administration. Early assessment of in vivo ADME properties provides critical data for the validation of in vitro screens (based on physicochemical and metabolic profiles) and establishment of in vitro / in vivo correlations. Coupled with the results from these in vitro screens, in vivo ADME data enables the early identification of compound liabilities, providing a basis for structural modifications or for the early initiation of development strategies to overcome these problems.

The Centre typically examines ADME properties for selected candidates within a chemical series after intravenous and oral administration to small laboratory animals such as rats and mice. A number of formulation approaches are used to facilitate solubilisation in vehicles suitable for intravenous administration. LC-MS and LC-MS/MS are predominantly used for the quantitation of compounds in plasma or other biological fluids such as urine or bile, providing rapid method development and high specificity and sensitivity. These methods also typically enable an initial indication of likely in vivo metabolites.

Culex Automated Blood Sampler (ABS)

The Centre uses the Culex^TM ABS system to collect blood and biological samples from conscious and free moving rats, greatly minimising animal stress. The system collects blood samples at pre-programmed times into sealed, refrigerated vials. Urine is also collected into chilled vials and faeces are separated by a stainless steel screen. Catheters are attached to a tether wire via a collar on the rat and the tether wire is, in turn, attached to a sensor assembly mounted on a counter-balanced arm above the cage. This arm moves up and down to accommodate the rearing behaviour common in rats and sensors monitor both rotational and rearing movement. If the rat moves in one direction, sensor activation causes a motor to engage, which turns the Raturn^® cage in the opposite direction, so that catheters do not become twisted or entangled.

Utilisation of the Culex^TM ABS (of which the CDCO has two) greatly enhances the conduct of in vivo studies, providing overnight sampling, flexible study design, high quality data and reduced animal handling.