Inhibition of first-pass metabolism in cancer chemotherapy: Interaction of 6-mercaptopurine and allopurinol

Zimm, Solomon; Collins, Jerry M.; O'Neill, Dondra; Chabner, Bruce A.; Poplack, David G.

doi:10.1038/clpt.1983.254

Cited by 160 publications

(80 citation statements)

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“…The production of 6-thiouric acid from 6-MP catalysed by xanthine oxidase is a third competing pathway for 6-MP but for 6-TG to be a substrate for this enzyme it has to undergo an additional metabolic step (guanase catalysed 2-deamination) and so the flux down this path is not as great as for 6-MP. No reduction in 6-TG dose is required with allopurinol coadministration (Lu et al, 1982;Zimm et al, 1983). The goal with any drug therapy is to achieve the desired biological effects whilst minimising or avoiding undesirable side effects.…”

Section: Discussionmentioning

confidence: 99%

Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?

Lennard

Davies²,

Lilleyman³

1993

Br J Cancer

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SummaryThe cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug -at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL).Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy.Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10-8 RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered.In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.

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Section: Discussionmentioning

confidence: 99%

Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?

Lennard

Davies²,

Lilleyman³

1993

Br J Cancer

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“…Administration of the xanthine oxidase inhibitor allopurinol increases the bioavailability of oral 6-mercaptopurine (Zim et al, 1983), increasing the amount available for conversion into nucleotide metabolite.…”

Section: Discussionmentioning

confidence: 99%

Azathioprine metabolism in kidney transplant recipients.

Lennard¹,

Brown²,

Fox³

et al. 1984

Brit J Clinical Pharma

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Sheffield S10 2JF 1 Azathioprine metabolite concentrations were studied in 54 kidney transplant recipients. Thirty-seven of these patients were studied over a 6 month period to investigate the intrapatient variation in metabolite concentrations. All patients had stable functioning grafts and normal peripheral white blood cell counts. 2 The metabolites measured were plasma 6-mercaptopurine and red blood cell 6-thioguanine nucleotide. 3 There was no correlation between azathioprine dose and plasma 6-mercaptopurine concentration but there was a significant correlation between dose and red blood cell 6-thioguanine nucleotide concentration (r, = 0.41, P < 0.005). The individual transplant recipient showed little variation in metabolite concentrations over several months. 4 Using this group as a control we studied metabolite concentrations in patients with kidney transplants who developed leucopenia. Our preliminary findings indicate that elevated red cell 6-thioguanine nucleotide concentrations, above the control range, can be associated with bone marrow depression.

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“…6MP undergoes hepatic metabolism and the first-pass effect is considerable (Zimm et al, 1983). MTX-induced hepatotoxicity, whether or not due to increased intestinal absorption or reduced clearance, could therefore impair 6MP breakdown, leading to treatment intensification.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia

Schmiegelow

Pulczynska²

1990

Br J Cancer

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Summary In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT)) during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT < 40 IU I -. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r > 0.70, P < 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk (Figure 1). One hundred and twenty-eight patients completed induction and consolidation therapy. Of these, 13 were excluded from this study due to major protocol violation during induction or consolidation therapy, refusal of MT by parents, AT not measured during MT, or lack of data (3, 1, 7 and 2 patients). Thus, 115 patients (67 boys and 48 girls) were eligible for analyses, with 56 cases of standard risk (SR), 39 cases of daily for 4 days); 6MP = oral 6-mercaptopurine (75 mg m-2 day-'); MTX = oral methotrexate (20 mg m-2 week-'); M = intrathecal methotrexate (12 mg m 2); pred/p = oral prednisone (60 mg m-2 day-'); -= 6-thioguanine (60 mg m 2 day-'); | / M = 500/1,000 mg MTX 24 h infusion with leucovorin rescue; V = vincristine (2 mg m2, max. 2 mg dose-'); XXXX = CNSirradiation (2,400 cGy).

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Inhibition of first-pass metabolism in cancer chemotherapy: Interaction of 6-mercaptopurine and allopurinol

Cited by 160 publications

References 0 publications

Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?

Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?

Azathioprine metabolism in kidney transplant recipients.

Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia

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