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Dear Group,
The proportion of a drug that enters the blood
circulation following oral ingestion can depend on the
activity and expression of the efflux pump
P glycoprotein MDR1 and metabolizing enzyme CYP3A4,
both of which are regulated by the orphan nuclear
receptor PXR (Also known as Xenosensor).PXR is known
to be activated by numerous xenobiotics such as
rifampicin, thereby causing increased expression of
MDR1 and CYP3A4 in enterocytes.
In addition to the intestinal absorption, Nuclear
receptors such as CAR, PXR or FXR are also known to
regulate the transporters and enzymes of the
hepatocytes.It would be appropriate to assess the
binding potential of drug with PXR receptor during
development in order to understand the drug
interaction when it is coadministered with the
substrates of Pgp/CYP 3A4. Receptor binding assays
with radio labelled drug is commonly used as a tool to
assess the ligands of the receptors.
Realizing the importance of Xenosensors, I would
appreciate if anyone from PharmPK group can address
the different techniques that are in use to assess the
ligands/NCEs of PXR or Xenosensors. Thanks in advance
Regards,
S Syed Mustafa,
Research Associate,
Drug Metabolism & Pharmacokinetics,
Discovery Research,
Dr Reddy's Lab Ltd,
Bollaram Road, Miyapur,
Hyderabad- 500049 INDIA
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Dear Mustafa and group
There are many different techniques to assess the ligands of
xenosensors. First and formost is what you have mentioned in your text -
In vitro
* radioligand binding assay.
* Reporter gene assay.
In vivo
* Humanoid mice
The time of conducting this assays in drug discovery is debatable
(whether early stage or after lead identification). As a matter of fact,
these assays are bracketed under FDA as safety assessment for the lead
(Drug interaction - Induction /Inhibition).
Further comments on this issue is most welcome.
Ansar Ali Khan, M.Sc.,
Research Scientist,
Drug Metabolism and Pharmacokinetics,
Glenmark Research Centre,
Plot No.-A-607, TTC, Industrial Area,
Mahape, Navi Mumbai-400 709,
India.
Phone No: 91-22-5590 2491/92 Extn.308
Fax No.: 91-22-5590 2318
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