The cytochrome P450 subfamily is comprised of three proteins CYP3A4, CYP3A5, and CYP3A7 which have been characterized. CYP3A4 is expressed in a majority of adult livers. In addition CYP3A subfamily members have been identified in enterocytes and contrivute to the first pass metablism of CYP3A substates. The antituberculosis agent, rifampin, is a potent inducer of CYP3A. Age and gender related differences in the extent of enzyme induction in animals and humans have been observed. Intestinal CYP3A plays an important role in the oral bioavailability of CYP3A substrates 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 isotopes, 15N3-midazolam, orally avoids inter-day variability in a subjects blood flow and allows the concurrent assessment of intestinal and hepatic CYP3A activity. The goals of this study are 1) to determine if elderly individuals have a decreased response to induction compared to young individuals 2) to determine if there are gender differences in the response to induction in elderly and young volunteers, and 3) to determine rifampin's principal site of induction using the simultaneous intravenous and oral administration of midazolam and a stable isotope.
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