Propoxyphene, Norpropoxyphene, and Proadifen (SKF-525A) Are Mechanism Based Inhibitors of CYP3A4, CYP3A5, and CYP3A in Human Liver Microsomes
type: CreativeWork
description: 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 vi 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 t…
abstract: 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 vi 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 t…
author: Riley, Anna Ruth
language: en_US
keywords: Clinical Pharmacology
date published: 2009-03-18T18:37:57Z
date modified: 2026-07-24T02:41:30Z
provider: IUPUI
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: IUPUI

PropertyValue
property ID: Handle
value: https://hdl.handle.net/1805/1855

PropertyValue
property ID: DOI
value: 10.7912/C2/286