In vivo effectiveness of several nucleoside transport inhibitors in mice and hamsters

The in vivo nucleoside transport inhibitory effects of 6-[(4-nitrobenzyl)-mercapto]purine ribonucleoside (NBMPR), used as its 5'-monophosphate derivative (NBMPR-P), dilazep, mioflazine and its derivatives soluflazine, R57974 and R75231, were investigated in BALB/c mice. The extent and duration of action were followed by assaying adenosine transport in blood cells sampled at time intervals following i.p. administration (ca. 20 mg/kg). Dilazep and R57974 were found to be short-acting inhibitors, while NBMPR-P and R75231 were similar in their action and caused essentially full inhibition of adenosine transport over a 4- to 5-h period. Mioflazine and soluflazine were rather ineffective, causing only partial inhibition. R75231 was also active after oral administration which, when repeated three times in 4-h intervals, resulted in essentially full transport inhibition up to 20 h following the initial dose. Effects of NBMPR-P, R57974 and dilazep on adenosine transport in blood cells were also measured in blood cells of hamsters after i.p. administration of the same doses. All three drugs caused full transport inhibition, but the action of dilazep and R75231 showed reversal within about 30 min and 2 h, respectively, while NBMPR-P caused full inhibition for at least 3-4 h. These results demonstrate the potential of the mioflazine derivative R75231 to be useful in vivo, possibly even after p.o. administration, for host protection against the actions of cytotoxic nucleosides used in experimental antiparasitic therapy or other studies requiring suppression of nucleoside transport.