Dear members,Back to the Top
We are looking for experimental methodology to find the relative
contribution of phase I and phase II metabolism of new chemical
entities. please suggest.
Metabolism and Pharmacokinetics,
Ranbaxy Research Laboratories
At first glance a look at the different profiles of metabolite obtainedBack to the Top
in microsomal incubation (only Phase I metabolism) against incubation
with hepatocytes (Phase I and II) might give you some hints.
Biopharmacopae design International
The one of most common ways to investigate the contribution of phase IBack to the Top
and phase II enzyme involved in the metabolism of NCE is to carry out
incubation of NCE in microsomes/hepatocytes in the absence and presence of ABT (1 mM). If you find significant depletion of NCE and inhibition by ABT that may
indicate involvement of P450s (phase I). If you observe, depletion of
NCE but no inhibition by ABT that would indicate involvement of non-P450
hepatic enzyme(s). In this case you have to identify the metabolite(s), if it an
oxidative metabolite, that would suggest involvement of enzyme such as
FMO, XO, AO, MAO etc. However, if it is a conjugated metabolite, you should
consider UGT, ST, NAT and other phase II enzymes.
Kishore K. Khan, Ph. D.
8609 Cross Park Drive
Austin, TX 78754
Tel: (512) 615 2332
Fax: (512) 834 7767
Dear Kishore,Back to the Top
Could you please quote the reference for the same, Since it sound good.
Thanks in advance,
Hi Tripta,Back to the Top
In vitro drug metabolism studies during the
preclinical screening give information on metabolite
identification, profile and stability, Phase II
metabolism, CYP induction/inhibition, drug/drug
interaction studies, CYP isoform identification.
Most widely used systems are expressed enzymes,
microsomes, isolated hepatocytes and tissue slices.
Dear Samiulla,Back to the Top
Please see reference below and references therein.
Curr Drug Metab. 2003 Dec;4(6):527-34.
Reaction phenotyping in drug discovery: moving forward with confidence?
Williams JA, Hurst SI, Bauman J, Jones BC, Hyland R, Gibbs JP, Obach RS,
Department of Pharmacokinetics, Pfizer Global Research and Development,
Plymouth Road, Ann Arbor, Michigan 48105, USA.
For the pharmaceutical industry, one of the challenges in evaluating the
risk of future compound attrition at the discovery stage is the
successful prediction of the major routes of clearance in humans. For compounds
cleared by metabolism, such information will help to avoid the development of
compounds that will exhibit large interpatient differences in
pharmacokinetics via 1). routes of metabolism catalyzed by functionally
polymorphic enzymes and/or 2). clinically significant metabolic
drug-drug interactions, in the later stages of development. The degree of
intersubject variability that is acceptable for a drug candidate is uncertain in the discovery stage where knowledge of other important factors is limited or
unavailable (i.e. therapeutic index, pharmacodynamic variability, etc).
Reaction phenotyping is the semi-quantitative in vitro estimation of the
relative contributions of specific drug-metabolizing enzymes to the
metabolism of a test compound. However, reaction phenotyping in the
discovery stage of drug development is complicated by the absence of
radiolabelled parent compound or metabolite bioanalytical standards
relative to later stages of development. In this commentary, some of the
approaches, based on published data, which can be taken to overcome these
challenges are discussed. In addition, knowledge of the molecular structure (i.e. specific chemical substituents), physicochemical properties, and routes of
clearance in animals can all help in making a successful prediction for the
routes of clearance in humans. In combination, the objective of these studies
should be to reduce to a minimum the risk of finding significant inter-patient
differences in pharmacokinetics at a later stage in development due to
significant metabolism by polymorphic enzymes or drug-drug interactions.
Consequently, this data should be used to avoid costly late stage
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