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ADME/DMPK Assays

LabREPROCELL is able to provide information on the absorption and metabolism characteristics of your compounds in ex vivo human respiratory, skin and gastrointestinal tissues by employing Ussing Chambers to mount intact sheets of human epithelium that retain all the relevant characteristics to model passive and active transport of substances.

The Ussing chamber allows measurement of short-circuit current through intact membranes, providing information on ion channel activity. Moreover, as the tissue is fresh and functional, transport and metabolism across various regions of the GI tract or trachea/lung can be estimated and compared with data from animal systems or CaCo-2 models. For example, you might wish to compare the absorption of your compound in the stomach, small intestine and large intestine. Read an Industry Insight article on the Ussing chamber system.

REPROCELL’s test systems are the only available method to predict the actual absorption and metabolism in intact fresh human tissues, the closest method to testing in the clinic.

Ussing chamber set-up

REPROCELL’s system is the only method that allows measurements of drug absorption, transporter effects and metabolism in the one experiment, making it more cost-efficient than individual assays. Moreover by using native human tissues it is the closest possible model of humans. We have industry's only database of human tissue assays, register here to view example data from a range of tissues and experimental models.

REPROCELL will create a protocol customised to meet your ADME needs, allowing confidence that your compounds will be successful in patients.

contact us today to discuss how to add commercial value through human data.


Gastrointestinal absorption and metabolism

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.

ADME/DMPK 1

ADME/DMPK 2

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, REPROCELL is able to mount the mucosal layer from multiple regions of the human GI tract and assess the 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 × Fg × 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 (February 22nd 2012). Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability, Topics on Drug Metabolism James Paxton, IntechOpen, DOI: 10.5772/31087. Available from: https://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.

REPROCELL is able to provide comparative pharmacology studies, translating preclinical animal data to humans. With REPROCELL'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 customized, study specific protocol to ensure that the experiment meets your objectives and provides the data you require to keep your project moving forward.

Please contact us for further information on our range of tests in fresh, functional human tissues.

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