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The following message was posted to: PharmPK
Hello:
Does anyone know the relative fraction of CYP 3A4 enzyme in gut (units or
micrograms enzyme/g protein or tissue) and liver? Is it possible to
determine the ratio of gut versus hepatic metabolism for a specific drug
after oral administration? Any references would be much appreciated. Thanks
to all.
Richard Knapp, Ph.D.
Aventis Pharma
ADME/DMPK
Route 202-206
PO Box 6800
Bridgewater, NJ 08807-0800
Voice (908) 231-2248, Fax (908) 231-4760
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The following message was posted to: PharmPK
Richard, check out this article:
Paine, M.F. et al. Characterization of Interintestinal and
Intraintestinal Variations in Human CYP3A-Dependent Metabolism, J.
Pharm. Exper. Therap. 283:1552-1562 (1997).
This article uses midazolam metabolism by human microsomes to
determine the regional distribution of Km, Vmax, Clint, in small
intestine and liver. There is also a calculation of total CYP3A
recovery and organ intrinsic clearance.
BTW, we have almost finished adding these types of metabolic
processes to the ACAT simulation model implemented in GastroPlus(TM)
(http://www.simulations-plus.com).
Mike
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
* Michael B. Bolger, Ph.D. Phone: (888) 266-9294
* Director of Life Sciences FAX: (661) 723-5524
* Simulations Plus, Inc.
* 1220 West Avenue J
* Lancaster, CA 93534-2902
* U.S.A.
* http://www.simulations-plus.com (OTC:SIMU)
* bolger.at.simulations-plus.com
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
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The following message was posted to: PharmPK
Dr. Knapp,
The relative contribution of hepatic and intestinal CYP3A to the metabolism
of orally-administered substrate can be determined by bioavailability
approach. If CYP3A probe (e.g. midazolam) is orally given, its hepatic and
intestinal extraction ratios serve as hepatic and intestinal CYP3A indices,
respectively. Several articles showed this concept. Please read Thummel KE
et al CPT 1996;59:491 or Gorski JC et al CPT1998;64:133. We developed more
convenient method than theirs. Our method will be appeared in next month's
issue of CPT as an abstract for this coming ASCPT meeting.
Good lurk.
Jang-Ik Lee, Pharm. D.
Department of Pharmaceutical Sciences, University of Pittsburgh
806 Salk Hall, 3501 Terrace St, Pittsburgh, PA 15261
Phone: 412) 648-9436 Fax: 412) 648-7671
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