ADME - Gastrointestinal

ADME - Gastrointestinal

Orally administered drugs continue to be the most common route of drug therapy. As development costs increase, models which can more effectively predict human bioavailability at an early stage in development have increasingly come to the fore.

It is also increasingly recognised that  the intestine not only influences absorption but is also an important site of first-pass metabolism that influences oral bioavailability (Ref 1). Common approaches do not accurately reflect the biology of the human small intestine- the site of absorption of most drugs.

Predicting the ‘Fraction absorbed’ (Fa) and metabolised (Fg) by the gastrointestinal tract

Functional intact human intestine mounted in Ussing chambers is the gold-standard technique for predicting both Fa and Fg in a single experiment. 

 

The figure and table above shows permeability (Papp) values for a range of low to high permeability compounds tested in fresh human duodenal mucosa set up in Ussing chambers, together with a curve that plots the in vitro Papp values against the clinical fraction absorbed (Fa), demonstrating a good correlation between the two.

By employing the Ussing Chamber, Biopta is able to mount the mucosal layer from multiple regions of the human GI tract and assess absorption and metabolism characteristics of your test compound.  The test compound is added to one side of the chamber and measured in the other, the permeability co-efficient is calculated and can then be compared to desired reference compounds.
 

Why use human tissues to predict gastrointestinal bioavailability?

Before a drug progresses to the clinic an estimation of the fraction reaching the systemic circulation (F, bioavailability) is required.  This can be expressed as:

F = Fa x Fg x Fh

Fa = fraction absorbed

Fg = fraction escaping gut clearance

Fh = fraction escaping hepatic clearance.

 

The benefits of using human fresh tissue to predict Fa and Fg include:

  • Data is generated in the actual site of drug absorption
  • Accurate metabolic and transporter profile
  • Avoids species differences
  • Adds commercial value during preclinical development
  • GI metabolism, binding, transport and permeability in one experiment
  • Reduces the risk of clinical failure 

In many instances, animal tissues from rats, dogs and non-human primates are used experimentally- but they often do not predict human bioavailability.

Rats: there is a good correlation between rat and human permeability; however, there is no correlation with oral bioavailability (Ref 2).

Dogs: there is a poor correlation between dog and human fraction absorbed (Ref 3).

Non-human primates: there is a good correlation between monkey and human permeability; however, there is a poor correlation with oral bioavailability as the expression of CYP enzymes is much higher in the GI tract of monkeys than it is in humans (Ref 4).

References and links to the original articles:

1. Ayman El-Kattan and Manthena Varma (2012). Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability, Topics on Drug Metabolism, Dr. James Paxton (Ed.), Available from: http://www.intechopen.com/books/topics-on-drug-metabolism/oral-absorption-intestinal-metabolism-and-human-oral-bioavailability-

2. Lennernas, H. Adv Drug Del Rev (2007) 59, 1103-1120

3. Chiou, W.L. et al. Pharm Rev (2000) 17, 135-140

4. Chiou, W.L. et al.  Pharmaceutical Res (2002) 19, 868-874

 

Download our brochure on the use of Ussing chambers to predict oral absorption and metabolism.

Biopta is able to provide comparative pharmacology studies, translating preclinical animal data to humans. With Biopta's help you can add commercial value and de-risk clinical development by ensuring that preclinical ADME data accurately predicts human absorption, transporters and metabolism.

We will work with you to create a bespoke, study specific protocol to ensure that the experiment meets your objectives and provides the data your require to keep your project moving forward.

Contact Biopta at info@biopta.com for further information on our range of tests in fresh, functional human tissues.

 

 

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