Permeability and Transporter Study

The oral absorption of drugs is related to their permeability, which can affect the rate and extent of absorption across the gastrointestinal tract and formulation strategies, and so on. High permeability generally leads to faster and more complete absorption, while low permeability may require formulation adjustments to increase passive permeability and/or inhibit efflux transporters for more absorption.

Permeability influences the ability of a drug to cross cell membranes, which in turn affects its distribution to various tissues and organs. High permeability facilitates extensive distribution, allowing drugs to reach target sites effectively, including those that are typically challenging to access, like the central nervous system. Conversely, low permeability can limit a drug’s distribution, potentially confining it to certain areas and impacting its therapeutic efficacy. In drug development, understanding and optimizing membrane permeability is essential to ensure that drugs can be efficiently delivered to their intended sites of action and achieve the desired therapeutic efficacy

WuXi AppTec DMPK has set up cell-based and vesicle-based models for P‑gp/BCRP substrate and inhibition assessment based on the recommendations of FDA, NMPA and other agencies. Cell-based models are suitable for relatively high permeability compounds, but may not be suitable for low permeable compounds, while the vesicle models can be used for low permeable compounds, but may fail to identify highly permeable compounds or highly non‑specific binding compounds as substrates. Therefore, we recommend selecting the appropriate model according to the properties of test compounds.

For ECCS (Extended Clearance Classification System) Class 1B and some ECCS Class 3B compounds, which are acids and zwitterions with molecular weight greater than 400, hepatic uptake is the predominant clearance mechanism, and hepatic uptake clearance should be evaluated to predict in vivo clearance. The use of hepatic metabolic clearance would underestimate the in vivo clearance of these compounds.