Disposition and metabolism of thiopurines III. beta-2'-Deoxythioguanosine and 6-thioguanine in the dog.

The anticancer agent beta-2' deoxythioguanosine (beta-TGdR, NSC-71261) has potential utility for the treatment of hematologic tumors resistant to 6-thioguanine (TG). We have studied the pharmacology and metabolism of these two agents in the beagle dog. [35S] beta-TGdR was administered as an IV bolus to five dogs at a dose of 10 mg/kg. Plasma radioactivity declined biphasically with an average terminal t 1/2 of 3.7 h. Cumulative urinary excretion of the radiolabel 5 h after administration was 19% of the total dose. In another four dogs that received 100 mg/kg (2.71 g), the average terminal plasma t 1/2 was 7.7 h and the 5-h cumulative urinary excretion was 28% of the total dose. [35S]Thioguanine, 5 mg/kg was similarly administered IV to three beagle dogs. The average terminal t 1/2 of [35S]TG and metabolites was 4.6 h, and the 5-h cumulative urinary excretion of the [35S] label was 47%. Similar studies were conducted in three beagle dogs that received the same dose of [8(14)C]TG. In these studies, however, the terminal phase t 1/2 of 14C in plasma was 1.9 h. Cumulative urinary excretion of the 14C was 40% in 5 h. Both TG and beta-TGdR were rapidly and extensively degraded. Neither of these agents and none of their metabolites was found in the cerebrospinal fluid in significant concentrations. In the dog, beta-TGdR was rapidly metabolized to TG and may serve as a slow release form of TG.