[Resistance to protease inhibitors: the role of the MDR gene].
MDR GENES: Overexpression of MDR genes leads to the production of glycoprotein P (PGP) that can use protease inhibitors as a substrate. This overexpression of MDR genes appears to be the cause, at least partially, of resistance to protease inhibitors by induction of very low intracellular inhibitor concentrations.
New compounds capable of inhibiting GPG have been tested. Ritonavir and verapamil reduce the impact of PGP efflux. Compared with verapamil, ritovavir appears to be more effective with a concentration-dependent action.
In vitro studies demonstrated that ritonavir can inverse the effect resulting from the expression of the MDR gene and the production of PGP, with restoration of significant intracellular levels of protease inhibitors, at least higher than obtained in the absence of ritonavir. Likewise, in vivo, it has been demonstrated that the more the gene is expressed, the less elevated is the intracellular concentration of the protease inhibitor.
Raffi
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Service Maladies infectieuses et tropicales, CHU Hôtel Dieu, Nantes.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001426:Bacterial Proteins; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D020014:K562 Cells / Q000378:metabolism; D026901:Membrane Transport Proteins; D019888:Nelfinavir / Q000494:pharmacology; D011480:Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001426:Bacterial Proteins; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; C104641:MRD protein, Streptomyces lavendulae; D026901:Membrane Transport Proteins; D011480:Protease Inhibitors; D014700:Verapamil; D019888:Nelfinavir; D019438:Ritonavir