APPLICATION OF DRUG METABOLISM IN DRUG DISCOVERY

1. MRS.REKHA AMIT BHALERAO
ASSISTANT PROFESSOR
PHARMACEUTICAL CHEMISTRY
PES MODERN COLLEGE OF PHARMACY, FOR LADIES

2. Drug metabolism has an important role in the
determination of the pharmacokinetic (PK) parameters
like oral bioavailability, clearance and the half-life of
the entity within the cell.
The drug metabolic studies help to screen the compounds
based on their metabolic rate and thereby help to proceed
with the in-vivo studies using rat, mouse, etc.

3.  The determination of the metabolite structure with
the help of LC/MS-MS and the metabolic
phenotyping i.e. the particular enzyme responsible
for the metabolism of the prospective drug, which
can be done using recombinant enzymes, gives a
much clearer idea about the metabolism of the
compounds and the information derived can be used
for further drug-drug interaction studies.

4.  Drug metabolism is very essential in the toxicity
studies. The persistence of the compounds in the
systemic circulation for long period causes toxicity
and the nature of the metabolites and the reaction of
the metabolites within the body, must be studied
thoroughly before the compounds progress to the
next stage of screening in drug discovery process. In
this way, it is seen that drug metabolic studies form
an integral part in drug discovery.

5.  Drug discovery is a process involving multiple
disciplines and interests. During the research
phase of drug discovery, usually a large number of
compounds are evaluated for biological activity
and toxicological potential in animal species.
Various types of problems with respect to
pharmacodynamics, pharmacokinetics, and
toxicity are commonly encountered at this stage.

6.  Drug metabolism, as a discipline participating
in a drug discovery team, can play an
important role in identifying factors underlying
the problems, facilitate the optimal selection of
compounds for further development, provide
information on metabolites for possible
improvement in drug design, and contribute to
the identification of the appropriate animal
species for subsequent toxicity testing

7.  Biotransformation is a process by which organic
compounds are transformed from one form to
another, aided by organisms such as bacteria,
fungi and enzymes.
Biotransformations are used as a valuable
strategy to build molecules, similar to parent
drug in the drug discovery programme.

8.  Biotransformations can also be used to synthesize
compounds or materials, if synthetic approaches are
challenging. Microbial biotransformations or
microbial biotechnology are extensively used to
generate metabolites in bulk amounts.
Biotransformation approaches and synthetic methods
provide a source for generating compounds around
core structures, which can be screened for various
biological activity studies.

9.  These studies help in screening and advancing the
compounds, through various stages of drug discovery
programme. Hence, biotransformation experiments
can be effectively utilized to synthesize more
compounds.

10.  The metabolic phenotyping of a prospective
drug is quite difficult, long-drawn and
expensive process.
 High-throughput screening of the prospective
drugs based on their metabolic stability is
carried out mainly using liver Microsomes in a
drug research lab.