Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this study is to determine if propoxyphene and norpropoxyphene
are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if
propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanismbased
inhibition is a type of irreversible inhibition that results from an inhibitor or its
metabolite binding to an enzyme during drug metabolism, which renders the enzyme
nonfunctional.
Propoxyphene is an analgesic that is frequently prescribed in the United States
and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of
CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not
been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed
drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and
norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in
these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes.
Time-dependent and concentration-dependent loss of activity of CYP3A was measured
by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the
greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5),
and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with
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CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was
a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and
CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver
microsomes fall within the range of reported therapeutic blood levels of propoxyphene,
with reversible inhibition constants (Ki values) above therapeutic blood concentrations
for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and
CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels,
except for blood levels after repeated dosing of propoxyphene at high concentrations. The
predicted change in the area under the plasma concentration versus time curve of an
orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated
for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times
higher with co-administration of propoxyphene based on in vitro kinetic parameters.
Propoxyphene and norpropoxyphene may cause adverse events when chronically
administered at high doses and/or when co-administered with other CYP3A substrates.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/1855 |
| Date | 18 March 2009 |
| Creators | Riley, Anna Ruth |
| Contributors | Queener, Sherry F., Jones, David R., Flockhart, David A., Willis, Lynn R. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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