In vitro oral drug permeation models: the importance of taking physiological and physico-chemical factors into consideration

ABSTRACT

Introduction: The assessment of intestinal membrane permeability properties of new chemical entities is a crucial step in the drug discovery and development process and a variety of in vitro models, methods and techniques are available to estimate the extent of oral drug absorption in humans. However, variations in certain physiological and physico-chemical factors are often not reflected in the results and the complex dynamic interplay between these factors is sometimes oversimplified with in vitro models.

Areas covered: In vitro models to evaluate drug pharmacokinetics are briefly outlined, while both physiological and physico-chemical factors that may have an influence on these techniques are critically reviewed. The shortcomings identified for some of the in vitro techniques are discussed in conjunction with novel ways to improve and thereby overcome some challenges.

Expert opinion: Although conventional in vitro methods and theories are used as basic guidelines to predict drug absorption, critical evaluations have identified some shortcomings. Advancements in technology have made it possible to investigate and understand the role of physiological and physico-chemical factors in drug delivery more clearly, which can be used to improve and refine the techniques to more closely mimic the in vivo environment.

KEYWORDS:

• In vitro model
• drug permeation
• physiological factors
• physico-chemical factors
• pharmacokinetics

Article highlights

• In vitro models are used in high throughput screening programmes to identify lead compounds for further clinical development.

• Many physiological factors are not present in in vitro models such as lack of blood supply, lack of nervous cell interactions, lack of mucus layer, variation in active transporters, absence of disease state and age effects.

• The physico-chemical properties of compounds have been used in some models as a basic indication of their drug likeness, but many compounds have been found to perform beyond the predictions of these models.

• Although some shortcomings of in vitro models have been addressed by refinement and improvements, the pharmacokinetic behaviour of some compounds still do not correlate well with the predictions from these models.

• A need exists for novel high throughput screening methods that can accurately predict the in vivo absorption of compounds beyond the limitations of conventional in vitro screening methods.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.