The metabolism of 6-dimethylaminopurine arabinoside (ara-DMAP), a potent inhibitor of varicella-zoster virus replication in vitro, was studied in rats and cynomolgus monkeys. Rats dosed intraperitoneally or orally with ara-DMAP excreted unchanged ara-DMAP and one major metabolite, 6-methylaminopurine arabinoside (ara-MAP), in the urine. They also excreted allantoin and small amounts (<4% of the dose each) of hypoxanthine arabinoside (ara-H) and adenine arabinoside (ara-A). The relative amount of each urinary metabolite excreted remained fairly constant for intraperitoneal ara-DMAP doses of 0.3 to 50 mg/kg of body weight. Rats pretreated with an inhibitor of microsomal N-demethylation, SKF-525-A, excreted more unchanged ara-DMAP and much less ara-MAP than did rats given ara-DMAP alone. Rats pretreated with the adenosine deaminase inhibitor deoxycoformycin excreted more ara-MAP and much less ara-H and allantoin.ara-MAP was shown to be a competitive alternative substrate inhibitor of adenosine deaminase (Ki = 16 ,IM).Rats given ara-DMAP intravenously rapidly converted it to ara-MAP and purine metabolism end products; however, ara-A generated from ara-DMAP had a half-life that was four times longer than that of ara-A given intravenously. In contrast to rats, cynomolgus monkeys dosed intravenously with ara-DMAP formed ara-H as the major plasma and urinary end metabolite. Rat liver microsomes demethylated ara-DMAP much more rapidly than human liver microsomes did. ara-DMAP is initially N-demethylated by microsomal enzymes to form ara-MAP. This metabolite is further metabolized by either adenosine deaminase, which removes methylamine to form ara-H, or by microsomal enzymes, which remove the second methyl group to form ara-A.Varicella-zoster virus (VZV) causes both chicken pox and shingles. Chicken pox is usually a mild disease in nonimmunocompromised patients, but shingles, the recurrent herpes zoster virus infection, can be very painful and severe. Both intravenous (i.v.) adenine arabinoside (ara-A) and oral (p.o.) or i.v. acyclovir have been used to treat VZV and herpes zoster virus infections. However, acyclovir is the preferred method of treatment for shingles (12,22). The effective doses of acyclovir for VZV are high compared with those used to treat herpes simplex virus, another herpesvirus (5, 10, 12). Therefore, a compound with both potent and selective activity against VZV would be useful.Two uridine analogs, (E)-5-(2-bromovinyl)-2'-deoxyuridine and (E)-5-(2-bromovinyl)-2'-uracil arabinoside, show potent antiviral activity against VZV (8) and have therapeutic potential. A 6-alkoxypurine arabinoside, 6-methoxypurine arabinoside, has anti-VZV activity with minimal in vitro cell toxicity, but it is extensively metabolized (2).We report here the disposition and metabolism of another active compound, an N6-alkyl-substituted adenine arabinoside. This compound, 6-dimethylaminopurine arabinoside (ara-DMAP), inhibits VZV replication in vitro (50% inhibitory concentration [IC50], 1 ,uM) without significant in vitro toxi...