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Hi:
We have a drug with a thiazolidinedione structure. In in-vitro studies it
inhibits recombinant CYP2C8, 9, 19 and CYP3A4 enzymes. With recombinant
human liver microsomes, it gets degraded with an extrapolated intrinsic
hepatic clearance of 9.4 ml/min/kg. However, it does not get degraded in
the presence of recombinant CYP1A2, CYP2C8, 9, 19, CTP2D6, and CYP3A4
enzymes under conditions known to adequately metabolize probe substrates.
Thus the metabolism observed in liver microsomes may be attributed to
non-CYP enzymes. Can someone please advise me on (1) What other non-CYP
enzyme systems could be metabolizing our drug, and (2) What studies we
should undertake to prove that? Any advise and suggestion will be highly
appreciated.
Thanks
Ananda
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Hello Ananda,
Is the metabolism of the compound NADPH independent?
If it is it may be catalyzed by Xanthine oxidases. You can confirm this
by using isovanillin as inhibitor of XO's.
If it is NADPH dependent then it may be catalyzed by FMO. You can
confirm the FMO involvement by heat deactivating the FMO at 500C(Cyp
enzymes are stable under these conditions) or by using Methimazole as an
inhibitor of FMO.
Hope this helps.
Sandeep Pusalkar
Millennium Pharmaceuticals, Inc.
Cambridge, MA 02474
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Hello Ananda,
Is the metabolism of the compound NADPH independent?
If it is it may be catalyzed by Xanthine oxidases. You can confirm this
by using isovanillin as inhibitor of XO's.
If it is NADPH dependent then it may be catalyzed by FMO. You can
confirm the FMO involvement by heat deactivating the FMO at 50 0C(Cyp
enzymes are stable under these conditions) or by using Methimazole as an
inhibitor of FMO.
Hope this helps.
Sandeep Pusalkar
Millennium Pharmaceuticals, Inc.
Cambridge, MA 02474
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)