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June, 2008
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Human tissue based models
for extrahepatic metabolism research
Asterand is the leading global supplier of human tissues and human tissue-based research services to pharmaceutical companies engaged in drug discovery and development.
Asterand's PhaseZERO
®
research services provide pharmaceutical companies with human tissue-based data to help select / support the progression of drug candidates with the goal of increasing the likelihood of clinical success. To expand our human ADMET services, we have recently developed a model to study metabolism in human lung (mixed parenchymal cells)
1
. We have also recently demonstrated phase I and phase II metabolism in gut (fresh, whole mucosa) and skin (keratinocytes)
2
. Work is ongoing to characterize the drug metabolism in human bronchial epithelial cells and human isolated enterocytes.
These models can be used to investigate and understand the impact of metabolism in tissues relevant to the site of administration of drugs / pro-drugs, prior to selection for further pre-clinical or clinical development. Most drugs are developed for oral administration and as such, supporting drug metabolism data are typically generated using hepatic models. However, following oral administration, the gut can also play a significant role in drug metabolism, yet often metabolism in human gut is not characterised prior to selection of compound for development. In addition, there are still a significant number of drugs developed or reformulated for administration via other routes, either in an attempt to avoid undesired first pass metabolism or to gain direct access to the relevant organ whilst minimizing systemic exposure. Whilst the liver is the organ responsible for the majority of drug metabolism, other organs also have metabolic capability. It is prudent therefore, to understand the impact of metabolism in tissues at the site of administration, as there may be first pass metabolism, which itself may lead to the production of a different profile of metabolites to those that may be generated in the liver. The major organs responsible for extrahepatic metabolism are listed in the panel below.
Route of administration
Key tissues
Asterand human tissue model
Oral
Liver
GI tract
hepatocytes
small / large intestine mucosa (preliminary model)
enterocytes (under development)
Inhaled
Lung
Nasal
lung parenchymal cells
bronchial / nasal epithelial cells (under development)
Dermal
Skin
keratinocytes (preliminary model)
1
Somers GI, Lindsay N, Lowdon BM, Jones AE, Freathy C, Ho S, Woodrooffe AJ, Bayliss MK, Manchee GR. (2007) A comparison of the expression and metabolising activities of phase I and phase II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metabolism and Disposition, 35(10): 1797-1805.
2
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