HepatoPac® Learning series: Part 2- METABOLITE IDENTIFICATION

May 16, 2017

For over a year now, SOLVO has been collaborating with Ascendance Biotechnology (formerly Hepregen) in the commercialization of their unique HepatoPac® plates in Europe and Asia. Encouraged by positive customer feedback and repeated orders from our customers, our own experience with the plates and the positive response to our webinar series in 2016, we have launched a series of Science Letters to further educate you on the use of this platform.

This week: Metabolite Identification using Micropatterned Co-Cultures of Primary Hepatocytes

The current industry standard is to measure metabolite production using primary hepatocytes (plated or in suspension) over a relatively short time course (typically 4-6 hours). However, some in vitro systems have shortcomings when used to predict the total in vivo metabolism profiles in humans:

  • Subcellular fractions are limited by the complement of DMEs present and thus do not provide a complete picture of the metabolism.
  • Some drugs are metabolized through multiple sequential reactions before excretion, but most in vitro systems may only reveal a limited number of sequential reactions.
  • Systems may not have sufficient long-term DME viability to turnover slowly and/or extensively metabolized molecules.
  • Standard incubation times may not be long enough to provide a complete metabolic profile, leading to poor predictions of in vivo metabolism.
  • Cell viability and rapid loss of metabolism function with time limits use of traditional plated or suspension hepatocytes, especially for low clearance or slowly metabolised molecules.
  • The presence of a metabolite in the circulation is also dependent on other dispositional and distributional properties of the metabolite, and this is difficult to predict/observe in traditional approaches where tissue/cell morphology has been extensively disrupted.

Therefore using traditional in vitro systems, it is entirely possible that clinically important metabolites may be observed only at very low levels, or perhaps not at all, with their relevance only realized at a much later stage in drug evaluation. HepatoPac® is an in vitro liver model designed to provide a superior assessment of the metabolite profile of candidate drugs. The proprietary patterning of hepatocyte “islands” in a “sea” of stromal cells enables stable enzyme activity for weeks, not hours or days. In addition, the HepatoPac® system maintains functional uptake and efflux transporter systems as well as a bile formation capability.

In this science letter, we show data from a study on 27 molecules in human liver microsomes, human liver S9 fraction, and human hepatocyte suspensions, comparing their success rates in the generation of the major human metabolites observed in radiolabeled human ADME studies. HepatoPac® is available for a variety of species (rat, dog, human) and can be delivered in different formats (24, 72, 96-well). Apart from HepatoPac® products, SOLVO also offers services using HepatoPac® plates.

Contact us to find out more!

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