Thioguanine dosing

Thioguanine is a purine analog that has been used as an alternative treatment for psoriasis when conventional therapies have failed. The typical dose is 80 mg twice weekly, increased by 20 mg every 2 to 4 weeks the maximum dose is 160 mg three times a week. Adverse effects include bone marrow suppression, GI complications (e.g., nausea, diarrhea), and elevation of liver fimction tests. 6-Thioguanine may be less hepatotoxic and therefore more useful than methotrexate in hepatically compromised patients with severe psoriasis. 

Factors that affect drug metabolism will influence the development of serious adverse effects. TPMT, one of the three enzymes that metabolize 6-MP, is encoded by a gene on chromosome 6 that contains functional polymorphisms. Multiple variants have been described ( 2, 3A, 3B, 3C, 3D, 4, 5, 6, 7, 10 31,32) that result in lower TPMT activity, leading to preferential metabolism of 6-MP by the HGPRT enzyme. This results in an increase in the amount of cytotoxic thioguanine nucleotides and greater myelotoxicity. There appears to be an allele dose-dependent... 

Methotrexate (Rheumatrex Dose Pack, TrexaU) Nelarabine (Arranon) Pemetrexed (Alimta) 6-Thioguanine [6-TG] (Tabloid)... 

Absorption of orally administered 6-thioguanine is slow and incomplete only approximately 30% of the oral dose is achieved in the plasma, peak levels being reached after 8 hours. Thioguanine is extensively metabolized prior to excretion. The elimination half-life is on the order of 80 minutes. 

Although 6-thioguanine is chiefly used in chemotherapy for acute myelocytic leukemia and other marrow-based malignancies, lower doses are very effective for moderate to severe psoriasis, particularly in... 

Dose-related myelosuppression is the major adverse effect produced by 6-thioguanine. Patients deficient in thiopurine methyltransferase (TPMT), a cytosolic enzyme required for metabolism of 6-thioguanine, are at heightened risk. Other adverse effects include gastrointestinal complaints and elevations of liver transaminases. There have been rare reports of more serious he-patotoxicity, including acute hepatitis, acute cholestasis, and hepatic venoocclusive disease. 

Thioguanine is slowly absorbed after oral administration parent drug levels are barely detectable, and peak levels of metabolites occur only after 6 to 8 hours. Total urinary excretion of metabohtes in the first 24 hours is 24 to 46% of the administered dose. 

Fig. 1. Outline of treatment strategy applied in the ALL-Berlin-Frankfurt-Munster (BFM) 95 study (1995-2000). Patients were assigned to standard-risk (SR), intermediate-risk (MR) and high-risk (HR) subgroups. Elements containing 6-mercaptopurine (6-MP) or 6-thioguanine (6-TG) are indicated in grey. Abbreviations PRED-GR, prednisone good response PRED-PR, prednisone poor response DEXA, dexamethasone VCR, vincristine DNR, daunorubicin HD-MTX, high-dose methotrexate LD-ARA-C, low-dose cytarabine SCT, stem cell transplantation.

The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were synthesized by Elion and Hitchings in the 1950s, and they play an important part in treatment protocols for leukemia (61,62,63,64). For no other than historical reasons, 6-MP is used in ALL while 6-TG is mainly used in acute myeloid leukemia (AML) or relapsed ALL. First-line treatment for childhood ALL usually includes several cycles of 6-MP at doses of 50-75 mg/m /d, starting as early as in consolidation/early intensification treatment until up to 36 months after diagnosis (1,2,3). 

LePage GA, Whitecar JP. Pharmacology of 6-thioguaninc in man. Cancer Res 1971 31 1627-1631. Konits PH, Egorin MJ, Van Echo DA et al. Phase II evaluation and plasma pharmacokinetics of high-dose intravenous 6-thioguanine in patients with colorectal carcinoma. Cancer Chemother Pharmacol 1982 8 199-203. 

In cultured human lymphocytes, the frequency of mutations for thioguanine resistance increases as a linear nonthreshold function of the x-ray dose over the range from 10 to 100 mGy (1 to 10 rad) (see Figure 7.1) and is essentially the same whether the dose is delivered in several fractionated exposures or in a single brief exposure (Grosovsky and Little, 1985). 

Jensen, D, and Ramel, C. (1980). Relationship between chemical damage of DNA and mutations in mammalian cells. 1. Dose-response curves for the induction of 6-thioguanine resistant mutants by low doses of monofunctional alkylating agents, x rays and UV radiation in V79 Chinese hamster cells, Mutat. Res. 73,339. 

Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. The dose of 6-MP or azathioprine should be reduced by at least half in patients taking allopurinol. 

Mercaptopurine and thioguanine are both given orally (Table 55-3) and excreted mainly in the urine. However, 6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation catalyzed by xanthine oxidase, whereas 6-TG requires deamination before it is metabolized by this enzyme. This factor is important because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used with chemotherapy in hematologic cancers to prevent hyperuricemia after tumor cell lysis. It does this by blocking purine oxidation, allowing excretion of cellular purines that are relatively more soluble than uric acid. Nephrotoxicity and acute gout produced by excessive uric acid are thereby prevented. Simultaneous therapy with allopurinol and 6-MP results in excessive toxicity unless the dose of mercaptopurine is reduced to 25% of the usual level. This effect does not occur with 6-TG, which can be used in full doses with allopurinol. 

CD-I mice were exposed to purified air or benzene by inhalation at 0.04, 0.1, or 1.0 ppm for 22 hours per day, 7 days per week for 6 weeks (Ward et al. 1992). The effects of in vivo exposure to benzene were evaluated by using an autoradiographic assay to determine the frequency of mutants which represent mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in spleen lymphocytes. At the end of the six weeks exposure period, lymphocytes were recovered from the spleens of the mice and cryopreserved prior to assay. Mutant cells were selected on the basis of their ability to incorporate tritiated thymidine in the presence of 6-thioguanine. The increased frequencies of mutant spleen lymphocytes were significant at the low and mid, but not the high dose, and the method does not take into account possible clonal expansion. Further evaluation of the induction of gene mutation at these dose levels seems warranted. 

Disposition in the Body. Incompletely and variably absorbed after oral administration. Rapidly activated by intracellular conversion to thioguanylic acid. Inactivated by methylation to aminomethylthiopurine and by deamination to thioxanthine. About 40% of an oral dose is excreted in the urine as metabolites in 24 hours only traces of thioguanine have been detected. 

Figure 18.9 shows the in vitro dose-effect curves for two thiopurine analogs, thioguanine (TG) and mercaptopurine (MP). The thiopurines are antimetabolites that are used in the treatment of acute leukemia. 

Pancreatitis has been reported after a progressive increase in dose of 6-thioguanine in a 10-year-old infant (39). She had had two previous episodes of pancreatitis after mercaptopurine. 

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). 

The usual initial dose is 2 mg/kg daily hy the oral route. If there is no clinical improvement or leukopenia after 4 weeks the dosage is increased to 3 mg/kg daily. In contrast to mercaptopurine, thioguanine may be continued in the usual dose when allopurinol is used to inhibit uric acid formation. 

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