Advancements in in vitro technologies and analytical instrumentation over the past decade allows us to apply a variety of in vitro based assays designed to rapidly assess metabolic and transport pathways, permeability and drug-drug interaction potential (these are some of the major factors contributing to both drug attrition and development delays). In vitro assays are ideal in early phase development as they typically can be conducted quickly and involve low compound usage – requiring just milligrams of material.

 

Early in vitro assays should be employed to assist lead optimisation and candidate selection (via IVIVE predictions of major metabolic pathways and clearance etc) and to help assess development 'risk' and now form an integral part of IND enabling studies (particularly DDI assessment).

 

Common in vitro systems available to the modern DMPK scientist include:

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Metabolizing systems:

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+Hepatocytes (characterised Human and non-human animal)

   +Suspension and culture systems

   +Contain all the hepatic DMEs

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+ Enterocytes for SI metabolism (cryopreserved and MetMax permeabilised cells)

+ Pulmonary fractions for lung metabolism

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+ Immortalized cell cell lines eg. HepG2

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+Microsomes

   +Liver and other organs

   +Contain the CYP and UGT enzymes (ER membrane bound enzymes)

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+S9 fraction

   +Contain both cytosolic and microsomal DMEs

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+Recombinant cDNA-expressed enzymes

+CYP, UGT, FMO

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Transporter systems:

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+ Transfected cell lines eg. MDCKII, HEK293

+ Immortalized cell lines eg. Caco-2

+ Vesicles

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Toxicity systems:

 

+ 3D cell models are increasingly being used to assess drug toxicity

 

(In vitro data should be continuously correlated with on-going in vivo ADME data (CLint > CLinvivo, and metabolite profiles) to assess IVIVE (in vitro-in vivo extrapolation) across species

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