USE OF RAT AND HUMAN IN-VITRO SYSTEMS TO ASSESS THE EFFECTIVENESS ANDENZYMOLOGY OF DEOXY-GUANINE ANALOGS AS PRODRUGS OF AN ANTIVIRAL AGENT

BRL 55792, BRL 55791, and BRL 55039 are prodrugs of an active anti-vir al agent 9-(3-hydroxypropoxy) guanine, (BRL 44385). The prodrugs were 6-deoxygenated analogues of BRL 44385 with ether groups substituted at the 9-position: BRL 55792 with an (isaprapoxymethyloxy)propoxy group, BRL 55791 with a (methoxymethyloxy)propoxy group, and BRL 55039 with an ethoxypropoxy group. Conversion of the prodrugs to BRL 44385 had be en demonstrated in vivo in rat and involved 6-oxidation followed by de alkylation. Metabolism was studied in rat liver in vitro systems to fi nd a model to evaluate BRL 44385 production. Rat hepatocytes performed both reaction steps and were used to assess which of the three prodru gs demonstrated greatest production of the active drug. BRL 55792 demo nstrated greatest conversion in vitro and this was in agreement with i n vivo data. The production of BRL 44385 from BRL 55792 was also demon strated in human hepatocyte incubations providing evidence that these reactions can occur in man thereby increasing confidence that BRL 5579 2 would be a suitable prodrug for human therapy. Further experiments w ere performed to investigate the enzymes involved in these conversions . The 6-oxidation step occurred in the cytosol. Use of allopurinol and menadione (xanthine and aldehyde oxidase inhibitors) indicated that t hese conversions were catalyzed exclusively by xanthine oxidase in the rat but mainly by aldehyde oxidase in man. The dealkylation reaction was detected in hepato cytes but not in homogenates or subcellular fra ctions. Inhibition of this reaction by aminobenzotriazole and ketocona zole (P-450 inhibitors) indicated that it was mediated by cytochrome P -450.