Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man
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Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, β-2′-deoxythioguanosine (β-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 β-TGdR in patients with cancer after intravenous administration. [35S]-β-TGdR (5.4 mg/kg, 200 mg/m2, 200 μCi 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 μCi 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 β-TGdR is merely a latent form of TG.
KeywordsSulfate Cancer Research Intravenous Administration Urinary Excretion Tumor Model
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- 1.Barranco SC, Humphrey RM (1971) The effects of β-2′-deoxythioguanosine on survival and progression in mammalian cells. Cancer Res 31:583Google Scholar
- 2.Bergman F, Kwietny-Govrin H, Ungar-Waron H, Kalmus A, Tamari M (1963) Biochem J 86:567Google Scholar
- 3.Householder GE, Loo TL (1971) Disposition of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, a new antitumor agent. Pharmacol Exp Ther 179:386–395Google Scholar
- 4.Iwamoto RH, Acton EM, Goodman L (1963) 2′-Deoxythioguanosine and related nucleotides. J Med Chem 6:684Google Scholar
- 5.Leonard EO, Orme-Johnson WH, McMurtray TR, Skinner CG, Shieve W (1962) 2-Hydroxy derivatives of some biologically active 6-(substituted) purines. Arch Biochem Biophys 99:16Google Scholar
- 6.Loo TL, Lu K, Benvenuto JA, Rosenblum MG (1981) Disposition and metabolism of thiopurines III: β-2′-Deoxythioguanosine and 6-thioguanine in the dog. Cancer Chemother Pharmacol 6:131–136Google Scholar
- 7.McCollister RJ, Gilbert WR, Ashton AM, Wyngaarden JB (1964) Pseudofeedback inhibition of purine synthesis by 6-mercaptopurine ribonucleotide and other purine analogues. J Biol Chem 239:1560Google Scholar
- 8.Moravek J, Nejedly Z (1960) Labeling of 6-mercaptopurine and 6-mercaptopurine riboside by an exchange reaction with elementary sulphur-35S. Chem Ind 530Google Scholar
- 9.Wolpert MK, Damle SP, Brown JE, Senycer E, Agrawall KC, Sartorelli AC (1971) The role of phosphohydrolase in the mechanism of resistance of neoplastic cells to 6-thiopurine. Cancer Res 31:1620Google Scholar