6-Thioguanine concentration

Western countries. However, thioguanine concentrations in this population were higher than in a previous study in 51 Japanese children [172 ]. There was a significant inverse correlation between white blood cell counts and thioguanine concentrations. Two patients had leukopenia with alopecia, and four had transiently increased serum activities of pancreatic enzymes, although no TPMT mutations were confirmed. 

Drug-drug iuteractious Allopurinol Treatment with allopurinol, a xanthine oxidase inhibitor, shifts metabolism towards higher thioguanine concentrations, reduces aminotransferase activities, and improves disease activity scores. In 41 patients with adverse reactions to full-dose thiopurines (25 with non-hepatic reactions and 16 with hepatic reactions), a combination of allopurinol with reduced-dose thiopurine bypassed many adverse drug reactions [173 ]. Remissions were achieved in 32 patients with a median follow-up of 41 (range 0.5-400) weeks. Patients who did not respond to combination therapy tended to fail early with the same adverse reaction. 

Monitoring drug therapy In 257 patients with ulcerative colitis who were treated with mercaptopurine as maintenance therapy, bone marrow suppression and other adverse reactions were monitored by regular measurement of erythrocyte concentrations of thioguanine [175 ]. Bone marrow suppression was seen almost exclusively at high thioguanine concentrations. Furthermore, there... 

Foradada and Estelrich [3.63] studied the encapsulation of thioguanine (TG) in three types of liposomes produced by extrusion, ethanol injection and dehydration-rehydration vesicles. The entrapment has been examined at three different concentrations (1, 0.1 and 0.01 mM) and at three different pH values (4.7,7.4 and 9.2). The dehydration-rehydration vesicles were found to be the optimum method to encapsulate TG, independent of the pH value. At pH 4.7, 12 mmol/mol of lipid were entrapped, while with the other methods a maximum of 3 mmol/mol of lipid has been achieved. The authors related this behavior to the formation of hydrogen bridges between the TG and the liposomes. 

The cell suspension is diluted in complete medium and 2 x 105 cells added per petri dish (10 petri dishes per treatment). 6-Thioguanine is added to the medium at a final concentration of lOpgml-1. 

It has been suggested that thioguanine s multistep inhibition, one step of which is the inhibition of phosphoribosylpyrophosphate amidotransferase, results in a profound lowering of the intracellular concentration of guanine nucleoside phosphates and that this depletion causes a marked depression in cellular metabolism that presumably would lead to cell death [91 ]. 

The concentration of toxin which causes a 50% reduction in cell bound dye after five days in culture. Cell lines used were H4TG, thioguanine-resistant rat hepatoma cells MDCK, Madin-Darb and canine kidney cells NIH3T3,NIH Swiss mouse embryo fibroblasts and KA31T, Kirsten strain of Moloney sarcoma virus-transformed 3T3 cells. 

Giverhaug T, Loennechen T, Aarbakke J. Increased concentrations of methylated 6-mercaptopurine metabolites and 6-thioguanine nucleotides in human leukemic cells in vitro by methotrexate. Biochem Pharmacol 1998 55 1641-1646. 

Dervieux T, Hancock ML, Evans WE et al. Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine. Leukemia 2002 16 209-212. 

Lennard L, Van Loon JA, Lilleyman JS et al. Thiopurine pharmacogenetics in leukemia correlation of erythrocyte thiopurine methyltransferase aetivity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 1987 41 18-25. 

Lancaster D, Patel N, Lermard L et al. Leucocyte versus erythrocyte thioguanine nucleotide concentrations in children taking thiopurines for acute lymphoblastic leukaemia. Cancer Chemother Pharmacol 2002 50 33-36. 

The metabolism of azathioprine is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug if dosage is not adjusted. 

Azathioprine and 6-mercaptopurine have a serum half-life of less than 2 hours however, the active metabolites, 6-thioguanine nucleotides, are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-mercaptopurine is observed in patients with inflammatory bowel disease. 

Wear protective gloves, clothing, and goggles. Dissolve 6 thioguanine (40 mg) in 80 mL of 3 M sulfuric acid (13.6 mL of concentrated sulfuric acid slowly added to 66.4 mL of... 

Of major concern is a report of an increased incidence of secondary brain tumors after radiotherapy in children with decreased TPMT activity phenotypes and/or high concentrations of thioguanine nucleotides in blood... 

FIGURE 18.9 Concentration-effect curves for the thiopurine analogs, mercaptopurine (MP, open symbols) and thioguanine (TG, closed symbols). Effect is the percentage of cells killed in vitro relative to an untreated control in MOLT 4 (squares), CCRF-CEM (ti iangles), and Wilson (cn des) leukemia cell lines. TG is 10-fold more potent than is MP. (Reproduced with permission from Adamson PC, Poplack DG, Balis EM. Leukemia Res 1994 18 805-10.)... 

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

In 16 patients with Crohn s disease taking a stable dose of azathioprine, plus sulfasalazine or mesalazine, mean 6-thioguanine nucleotide concentrations fell significantly over 3 months withdrawal of the aminosalicylates had no effect on the clinical and biological evolution of Crohn s disease in these patients (102). 

Lilieyman JS. Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia a comparison of haematological toxicity and drug metabolite concentrations. Br J Haematol 1998 102(2) 439-43. 

Pike NG, Franklin CL, Mays DC, Lipsky JL, Lowry PW, Sandborn WJ. Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methyhnercaptopurine nucleotides in blood. J Chromatogr 2001 757 1-9. 

Thioguanine is similar to 6-mercaptopurine in its action. The most active form is 6-thio-GMP, which inhibits guanylate kinase and, at higher concentrations, IMP dehydrogenase. Thio-IMP and thio-GMP also inhibit PRPP amidotransferase. 

Clinical response to mercaptopurine is related to whole-blood concentrations of the metabolite 6-thioguanine, and hepatotoxic-ity is correlated with another metabolite, 6-methylmercaptopurme. Metabolic inactivation of azathioprine and mercaptopurine occurs by thiopurine S-methyltransferase, which exhibits genetic polymorphism. Enzyme-deficient patients are at greater risk of bone marrow suppression from these agents. Determination of enzyme activity may be necessary to determine which patients require lower doses of these agents. 

Lancaster DL, Ratel N, Lennard L, Lilleyman JS. 6-Thioguanine in children with acute lymphoblastic leukemia Influence of food on parent drug pharmacokinetics and 6-thioquanine nucleotide concentrations. Br. J Clin Rharmacol 2001 51 531-539. 

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