Modification by nitrobenzylthioinosine-5'-monophosphate of pseudoisocytidine pharmacokinetics in mice and rats through inhibition of membrane transport.
In isolated, perfused mouse livers, initial rates of uptake of [2-14C]pseudoisocytidine (PIC), measured during the first 15 secs of perfusion were markedly reduced when the perfusion medium contained 5 X 10(-6) M nitrobenzylthioinosine (NBMPR), a potent inhibitor of nucleoside transport. A similar inhibition of PIC uptake occurred when mice were treated with NBMPR-P (the 5'-monophosphate of NBMPR) at doses greater than 0.2 mg/kg ip injected 30 mins prior to the liver perfusion assay. However, in vivo studies showed that a late effect of NBMPR-P was enhancement in PIC levels in liver and other tissues in mice and rats, relative to levels in animals that had not received NBMPR-P. Increases in incorporation of PIC into RNA reflected the NBMPR-P-induced increases in tissue levels of PIC. NBMPR-P and other inhibitors of nucleoside transport may have therapeutic applications in manipulation of the pharmacokinetic behavior and toxicity of nucleoside drugs.
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism*; D003562:Cytidine / Q000378:metabolism*; D007288:Inosine / Q000031:analogs & derivatives*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009705:Nucleosides / Q000378:metabolism; D010477:Perfusion; D012313:RNA / Q000378:metabolism; D051381:Rats; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology*
D009705:Nucleosides; D013873:Thionucleotides; D013868:Thioinosine; D007288:Inosine; D003562:Cytidine; D012313:RNA; C028318:nitrobenzylthioinosine 5'-monophosphate; C012518:pseudoisocytidine