The potential impact of drug transporters on nucleoside-analog-based antiviral chemotherapy.
Several ATP-binding cassette (ABC) transporters can transport drugs out of cells against steep concentration gradients resulting in resistance to the drugs transported. Recent work has shown that at least three members of the family of human Multidrug Resistance-associated Proteins (MRPs), MRP4, 5 and 8, are able to transport some nucleoside-monophosphate analogs. This can result in resistance to the base, nucleoside or nucleotide precursors of these results, at least in cell lines with high levels of transporter. The affinity of these transporters for the nucleotide analogs studied thus far is relatively low (millimolar rather than micromolar), and this limits their potential impact on the resistance. We briefly review how ABC transporters in general, and MRPs in particular, could affect the disposition and cellular accumulation of antiviral compounds.
Borst
P
P
Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. P.Borst@nki.nl
Balzarini
J
J
Ono
N
N
Reid
G
G
de Vries
H
H
Wielinga
P
P
Wijnholds
J
J
Zelcer
N
N
D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000502:physiology; D024882:Drug Resistance, Viral; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009705:Nucleosides / Q000378:metabolism* / Q000494:pharmacology*; D009712:Nucleotides, Cyclic / Q000378:metabolism / Q000494:pharmacology
D000998:Antiviral Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009705:Nucleosides; D009712:Nucleotides, Cyclic; C120809:ABCC5 protein, human