CRISPR™ MDCKII Cell Lines Development for Bioavailability and DDI Assessments

Описание: Permeability Screening is The role of P-glycoprotein (P-gp) and breast cancer related protein (BCRP) is well known in Drug-Drug Interactions. Evaluation of whether an investigational drug is a substrate or inhibitor of transporters is a regulatory requirement. The United States Food and Drug Administration (FDA) Guidance on Drug-Drug Interactions states that if drugs are highly soluble and highly permeable, the drug must be evaluated for interactions with P-gp and BCRP. Cell-line models (such as Caco-2 or MDCKII) or Artificial Membrane (such as PAMPA) models are used for evaluation of permeability. Caco-2 or MDCKII can be further extended to evaluate if an investigational drug is a substrate or inhibitor of P-gp or BCRP through determination of efflux ratios and subsequent reduction in efflux ratio. However, there are shortfalls of both Caco-2 and MDCKII cell lines that may not allow for full characterization of investigational new drugs. For example, Caco-2 expresses a wide variety of transporters that may not be able to be specifically probed and inhibited for determination of efflux. MDCKII also endogenous expression of canine versions of human transporters which share significant sequence similarity.