Pharmacokinetics and metabolism of beta-2'-deoxythioguanosine and 6-thioguanine in man.
Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, beta-2'-deoxythioguanosine (beta-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of beta-TGdR in patients with cancer after intravenous administration. [35S]-beta-TGdR (5.4 mg/kg, 200 mg/m2, 200 microCi total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 microCi total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6-thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that beta-TGdR is merely a latent form of TG.
D000493:Allopurinol / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D009369:Neoplasms / Q000378:metabolism; D013866:Thioguanine / Q000378:metabolism*; D013872:Thionucleosides / Q000378:metabolism*
D000970:Antineoplastic Agents; D013872:Thionucleosides; D000493:Allopurinol; C010438:beta-2'-deoxythioguanosine; D013866:Thioguanine; D003849:Deoxyguanosine