Ex vivo compound profiling

The advantage of pituitary cell incubation with test compounds of suspected endocrine activity is that useful initial information can be provided rapidly, especially for compounds that show neuroendocrine modulating activity, e.g. neuroleptics and dopamine receptor agonists. The response at a clearly defined cellular level needs than to be compared with the response in intact animals, where multiple feedback loops are operating, and may markedly changed their response profile when the test result is compared in vitro and in vivo. The possibility of using pituitary cells ex-vivo from treated animals should always be kept in mind. 

Perfused organs Phase I and II present, whole metabolic profile observed, best correlation to in vivo expensive, ex vivo animal trial, complex methodology, high technical effort, batch variability, more complicated than enzyme-only system, quality control, limited use for multiple compounds... 

Ex vivo binding experiments indicated that compound 35 could successfully occupy brain H3 receptors at a submicromolar concentration following oral administration in rats (Figure 18.10). All compounds showed favorable logD values with low in vitro metabohc clearance and good Caco-2 permeabiUty. The pharmacokinetic profile of 35 was consistent with its adequate physicochemical... 

The compound displayed promising ex vivo duration of action in guinea pig trachea strips as well as a good systemic pharmacokinetic profile in terms of in vivo clearance and bioavailability from fraction swallowed (CL 130ml/min/kg F <5%). From overlays with salmeterol, and also the feet that 17 is isohpophiUc with salmeterol, it was concluded that both the exosite and the microkinetic theories could potentially explain its apparent duration of action and 17 was selected as a clinical candidate. 

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