Many P-glycoprotein substrates do not inhibit the transport process across cell membranes.
Xenobiotica
; 33(2): 131-40, 2003 Feb.
Article
em En
| MEDLINE
| ID: mdl-12623756
ABSTRACT
1. The critical role of P-glycoprotein (P-gp) in the clinical exposure of many pharmaceuticals and toxins has become widely appreciated. The P-gp-mediated influence can often be more significant than that of other well-known xenobiotic defence enzymes in both breadth and impact. The inhibition of P-gp, therefore, has often been examined by testing a compound for its influence on the P-gp-mediated transport of some marker substrate, often the compound is also evaluated for its active efflux mediated by P-gp. 2. Although a substrate for a xenobiotic defence enzyme is logically presumed to be an inhibitor of that enzyme toward an alternate substrate, that is not necessarily the case with a transmembrane active efflux transporter. A substrate that is ejected from the cytosolic side of the membrane bilayer that does not rapidly cross the membrane by passive diffusion back into the cell interior will not occlude the substrate binding site. Hence, some substrates may not significantly affect the overall P-gp function of causing a concentration gradient by efficient net transport. A wide variety of compounds that are documented as substrates of P-gp are characterized here as having no effect on the ability of P-gp to transport several conventional P-gp marker substrates. 3. Transbilayer passive diffusion apparently dictates the ability of a P-gp substrate to be an inhibitor, as described herein based on relative rates of transport (active efflux versus passive re-entry) and the interaction of amphipathic compounds with the cell membrane. 4. The portion of P-gp substrates whose disposition is dependent on P-gp function and which are not also inhibitors is striking. It is therefore important to characterize both the efflux rate parameters and those of inhibition. 5. This report affords a valuable list of known P-gp substrates that are non-inhibitors.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Subfamília B de Transportador de Cassetes de Ligação de ATP
Limite:
Animals
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Estados Unidos