Disposition and metabolism of thiopurines - III. β-2′-Deoxythioguanosine and 6-thioguanine in the dog

The anticancer agent β-2′ deoxythioguanosine (β-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]β-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 [8¹⁴C] 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 β-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, β-TGdR was rapidly metabolized to TG and may serve as a slow release from of TG.