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SCDMDG presents:

Regulation Of Intestinal CYP3A By VDR: Implications And Safety Of Oral Therapeutics

Dr. Kenneth E. Thummel, Ph.D
Professor and Chair
Department of Pharmaceutics
University of Washington
Seattle, Washington

Biotransformation of drugs and other xenobiotic molecules by hepatic and intestinal CYP3A4 can be a major determinant of the systemic bioavailability and clearance of orally administered drugs. The expression and function of CYP3A4 in these tissues is most likely influenced by multiple mechanisms of control, including those that involve endogenous and exogenous modifiers of gene transcription that exert their effects through activation of nuclear hormone receptors.

Through a series of cell-based and in-vivo studies we, and others, have shown that CYP3A4 expression within enterocytes of the small intestine may be activated through a vitamin D receptor mediated signaling pathway (5-8). Moreover, CYP3A4 can catalyze the catabolism of the most active receptor ligand, 1α,25-dihydroxy vitamin D3, providing the possibility of feedback control of important genomic effects of the hormone in this tissue (9,10).

Two questions emerge from these observations:

  1. Does variability in the VDR signaling pathway contribute to inter-individual differences in basal intestinal CYP3A4 expression?
  2. Does modification of CYP3A4 expression by exogenous stimuli (e.g., drug activators of hPXR) affect the local disposition of vitamin D and, in turn, its genomic effects and contribute to adverse drug reactions?

In this presentation, the speaker will review evidence for the control of intestinal CYP3A4 by VDR and the proposed feedback control of vitamin D genomic effects through CYP3A4-dependent vitamin D metabolism. These issues will also be discussed in the broader context of understanding sources of inter-individual differences in both efficacious and adverse drug response.

Kenneth Thummel is Professor and Chair of the Department of Pharmaceutics, School of Pharmacy, University of Washington. He received a Bachelor of Science degree in Chemistry from Boise State University in 1981 and a Ph.D. in Pharmaceutical Science from the University of Washington in 1987. He completed a post-doctoral fellowship with Dr. John Schenkman at the University of Connecticut Health Science Center, studying in the field of cytochrome P450 structure and function. In 1989, he joined the faculty at the University of Washington and was promoted to the rank of Professor in 2001. In 1997, he was appointed to the Institute for Public Health Genetics, and currently serves as the program deputy director.

Date: Wednesday, May 7, 2008 – 5:00 p.m. (Buffet), 7:00 p.m. (Presentation)
Location: Biogen Idec
Price: $15 Advance Registration, $15 At the Door (includes buffet dinner and soft drinks/beer/wine)

Space is Limited — Register Early to Guarantee Your Attendance!


Prior presentations:

Speaker Topic Date
Dr. Anthony Lu, PhD Why Is The Liver Microsomal Cytochrome P450 Such A Versatile And Unique Enzyme? September 12, 2007
Dr. Scott Obach, PhD Leveraging ADME Data In Metabolites In Safety Testing (MIST) April 18, 2007
Dr. Sidney Nelson, PhD Drug Metabolism and Chemical Structural Alerts September 27, 2006
Richard B. Kim, MD Relevance and Utility of Transporters to Drug Discovery and Development September 21, 2005
Dr. Frederick P. Guengerich, Ph.D. Human Cytochrome P450 2A6 as a Case History:  Flavors, Smoke, Blue Roses, New Drugs & Basics of a P450 April 27, 2005
Dr. Leslie Benet, Ph.D. Predicting Drug Disposition via Application of BCS: Transport/Absorption/Elimination Interplay and BDDCS September 29, 2004
Dr. Christopher A. Lipinski, Ph.D. ADME/Tox: How Low Can You Go And How Do You Recover? April 21, 2004


Our May 2008 meeting is generously sponsored by:

BioFocus QPS Pharmaceuticals Xenotech
BD Biosciences Celsis In Vitro Technologies CellzDirect Invitrogen Corporation
Biogen Idec    

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