The human cytochrome P450 3A subfamily is comprised of three proteins CYP3A4, CYP3A5, and CYP3A7 which have been characterized in detail. CYP3A4 is expressed in a majority of adult livers and metabolizes approximately 40% of drugs in current use. In addition CYP3A subfamily members have been identified in enterocytes and contribute to the first pass metabolism of CYP3A substrates. Intestinal CYP3A plays an important role in the oral bioavailability of CYP3A substates such as midazolam, nifedipine, and cyclosporine A. Midazolam is a 1,4 imidazobenzodiazepine which is a selective CYP3A subfamily member substrate and is currently employed as an in vivo probe for CYP3A hepatic and intestinal activity. The simultaneous administration of midazolam intravenously and its stable isotope, 15N3-midazolam, orally avoids inter-day variability in a subjects blood flow and allows the concurrent assessment of intestinal and hepatic CYP3A acitivity. The goals of this study are to determine if elderly females, with or without estrogen replacement therapy, exhibit altered drug clearance and bioavilability due to differential changes in intestinal (oral route) and hepatic (intravenous route) acitivity of CYP3A enzymes when compared to young females. The 72 hour dextromethorphan N- demethylation urinary ratio can also be used as an in vivo CYP3A probe, but further validation must be carried out.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
3M01RR000750-27S1
Application #
6291047
Study Section
Project Start
1998-12-01
Project End
1999-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
27
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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