Drug metabolism is an important determining factor in identifying potential liabilities early during drug discovery. Metabolites could potentially contribute and alter the pharmacological activity of the drug and/or its toxicity. Recent regulatory guidance such as “Metabolites in Safety Testing” (MIST) by FDA and ICH, encourages pharmaceutical industry to identify, characterize and quantify drug metabolites during early drug discovery, in order to avoid potential metabolite related safety issues in late phase drug development.
In vitro studies using animal and human hepatic sub-cellular fractions (S9 and microsomes) and cells (hepatocytes) are used as models to identify potential human metabolites during early discovery. Later metabolite identification in preclinical species such as rat, dog, mice, etc. aid in the selection of a suitable animal model for nonclinical toxicity studies that mimic the human metabolic profile very closely, preferably encompassing all metabolites observed in humans. These studies are aimed at fulfilling the regulatory criterion for identifying and quantifying any metabolite with an exposure level ≥10% of the parent, during preclinical safety and clinical studies.
As a result, metabolite profiling has become a crucial component in drug discovery and development and the “Metabolite Identification Group” at Piramal Healthcare Research Centre plays a pivotal role in drug discovery and development by providing this support. In the discovery phase, the tentative metabolic profile of an NCE in different in vitro and in vivo biological matrices is evaluated for:
- Assessing the potential risks that could be associated by the generation of toxic metabolites
- Selection of an animal model for nonclinical toxicity studies.
Subsequently, at later development stages, the major and/or metabolites of significance are isolated and characterized both chemically and pharmacologically to confirm their contribution in the clinical efficacy and toxicity of the drug.
In addition, tissue imaging to evaluate the spatial and temporal distribution of the drug and its metabolites is also performed through mass spectrometry based MALDI imaging technique.
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Selected publications:
- Nilanjana Biswas. Solid forms and pharmacokinetics. In: Johan Wouters, Luc Quéré, Eds. Pharmaceutical Salts and Co-crystals. The Royal Society of Chemistry, 2011:128-153.
http://www.rsc.org/shop/books/2011/9781849731584.asp