Pharmacokinetics


In vitro Assays

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  • Kinetic (Turbidometric) solubility

    • Poor solubility can limit the absorption of compounds from the gastrointestinal tract which reduces oral bioavailability. The quality of the data generated from the in vitro assays can also be affected by poor solubility.
    • While thermodynamic solubility is useful when preparing a data package for a proposed development candidate, kinetic solubility is appropriate for high throughput in vitro assays for early discovery.
    • We are able to perform the assay at different pH values. to mimic the conditions present in the stomach and small intestine respectively. For ionizable compounds, aqueous solubility is dependent on pH. If a compound has no ionizable groups then its solubility will be unaffected by the pH of the buffer.
    • Download assay details

 

  • Microsomes (Mouse, Rat, Human, etc.)
    • The liver is a key site of drug metabolism. Approximately 60 % of marketed compounds are cleared by hepatic CYP-mediated metabolism.
    • Liver microsomes are subcellular fractions which contain membrane bound drug metabolizing enzymes.
    • Where clearance is primarily hepatic, microsomes can be used to rank order and to develop a SAR to manipulate that clearance.
    • The use of species-specific microsomes can be used to enable an understanding of interspecies differences in drug metabolism.
    • Download assay details

 

  • Plasma stability (Mouse, Rat, Human, etc.)
    • Determination of the stability of new chemical entities in serum is important as compounds (with the exception of pro-drugs) which rapidly degrade in serum generally show poor in vivo efficacy.
    • Instability in plasma can result in misleading in vitro data which can be difficult to interpret (e.g., plasma protein binding data or cell-based assays).
    • Compounds with the following functional groups tend to be more susceptible to hydrolysis in plasma: esters, amides, lactones, lactams, carbamides, sulfonamides, and peptic mimetics.

 

  • Plasma Protein binding (Mouse, Rat, Human, etc.)
    • Binding to plasma proteins influences the way in which a drug distributes into tissues.
    • Extensive plasma protein binding limits the amount of free compound available to access sites of action in the cell, and metabolism and elimination may be slower.
    • Equilibrium dialysis is the accepted method to understand plasma protein binding.

 

In Silico Models:


In vivo Assays