Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside

Loo, Ti Li; Luce, James K.; Sullivan, Margaret P.; Frei, Emil

doi:10.1002/cpt196892180

Cited by 97 publications

(19 citation statements)

References 3 publications

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“…The drug is not transported in significant amounts into the spinal fluid when administered orally. The plasma half-life of 6-MP was reported to be 47 min in adults and 21 min in children [105]. The cause of this discrepancy between these two age-groups is not yet known.…”

Section: -Mercaptopurinementioning

confidence: 90%

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Chemotherapy of Childhood Acute Lymphoblastic Leukemia

Bell¹,

Whitehead²

1986

Dev Pharmacol Ther

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This article reviews current chemotherapy of childhood acute lymphoblastic leukemia, with particular emphasis on the pharmacology of the drugs used. In the perspective of the overall treatment plan, the use, mode of action, toxicity and pharmacology of prednisone, vincristine, L-asparaginase, cyclophosphamide, 6-mercaptopurine, methotrexate and cytosine arabinoside are reviewed. Issues relating to central nervous system prophylaxis, drug compliance, drug resistance, and treatment failure are considered.

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Section: -Mercaptopurinementioning

confidence: 90%

“…Absorption of 6-MP from the intestine is unpredictable with between 16% [104] to 50% [105] of the dose reaching the systemic circulation. The drug is not transported in significant amounts into the spinal fluid when administered orally.…”

Section: -Mercaptopurinementioning

confidence: 99%

Chemotherapy of Childhood Acute Lymphoblastic Leukemia

Bell¹,

Whitehead²

1986

Dev Pharmacol Ther

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“…There have been several previous attempts at measuring azathioprine or 6-MP in plasma (Hamilton & Elion, 1954;Finkel, 1967;Loo, Luce, Sullivan & Frei, 1968;Coffey, White, Lesk, Rogers & Serpick, 1972;Spreafico, Donelli, Bossi, Wecchi, Standen & Garattini, 1973;Bailey, Wilson & Johnson, 1975) but these assays have either lacked specificity or sensitivity or both and have been of little value in studying azathioprine pharmacokinetics in patients. The present assay for 6-MP is the first to be developed with sufficient sensitivity and specificity to allow kinetic studies to be done on patients taking therapeutic doses of azathioprine (Maddocks, 1975).…”

Section: Discussionmentioning

confidence: 99%

Assay of azathioprine, 6‐mercaptopurine and a novel thiopurine metabolite in human plasma.

Maddocks¹

1979

Brit J Clinical Pharma

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1 A simple, specific assay for 6-mercaptopurine (6-MP) in human plasma with a sensitivity of 10 ng/ml (66 nmol/1) has been developed. 2 6-MP was extracted directly from plasma into toluene using a novel extraction procedure. This involves conversion of 6-MP into a phenyl mercury derivative by its reaction with phenyl mercuric acetate in alkaline plasma and extracting into toluene. Back-extraction of the toluene layer with 0. IN HC1 regenerates 6-MP, which is then oxidised to purine-6-sulphonate and assayed fluorimetrically. 3 This assay has been modified to measure azathioprine and a new thiopurine metabolite in plasma. 4 In a kidney transplant patient given azathioprine, 50 mg i.v., conversion to 6-MP was rapid and the plasma half-life of 6-MP was 36 min. 5 These assays are suitable for studying the pharmacokinetics of azathioprine in patients with kidney transplants. The 6-MP assay should also prove useful for studying the pharmacokinetics of the drug in patients with leukaemia.

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“…6-Mereaptopurine riboside is converted into 6-methylmercaptopurine riboside (MeMPR) t which can be phosphorylated intraceliul MetIMP by adenosine kinase [12,13] and \ not be broken down by purine nucleoside ] ylase [14]. The methylation by TPMT of 6-methylmercaptopurine (MeMP), which cytotoxic action, results in detoxification oi [3].…”

Section: Involvement Of Thiopurine Methyltransferase In the Metabolismentioning

confidence: 99%

Thiopurine methyltransferase: a review and a clinical pilot study

Keuzenkamp-Jansen

Leegwater

Abreu

et al. 1996

Journal of Chromatography B: Biomedical Sciences and Applicatio

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Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of 6-mercaptoptirine (6MP), which is used in the treat men t of acute lymphoblastic leukemia (ALL). TPMT catalyzes the formation of methylthioi nosine monophosphate (MetlMP), which is cytotoxic for cultured cell lines, and it plays a role in detoxification of 6MP, Population studies show a genetic polymorphism for TPMT with both high and low activity alleles. About 1 of 300 subjects is homozygous for the low activity. The function TPMT plays in detoxification or therapeutic efficacy of 6MP in vivo is not clear. In this article the genetic polymorphism of TPMT is reviewed and the contribution of TPMT to the cytotoxic action, or detoxification, of 6MP in children with ALL is discussed. Induction of TPMT activity has been described during the treatment for ALL. We performed a pilot study on the influence of higlvdose 6MP infusions (1300 m g/m 2 in 24 h) on TPMT activity of peripheral blood mononuclear cells (pMNC) of eleven patients with ALL. The TPMT activities were in, or, above the normal range. There was no statistically significant difference between the TPMT activities before and after the 6MP infusions. MetlMP levels in pMNC increased during successive courses. This might be explained by TPMT induction, but other explanations are plausible as well. Twenty five percent of the TPMT assays failed, because less than the necessary 5*i0f' pMNC could be isolated from the blood of leukopenic patients. Red blood cells can not be used for TPMT measurements, since transfusions are frequently required during the treatment with 6MP infusions. Therefore, the influence of high-dose 6MP infusions on TPMT activity can only be investigated further when a TPMT assay which requires less pMNC has been developed.

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Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside

Abstract: Gastrointestinal absorption of

Cited by 97 publications

References 3 publications

Chemotherapy of Childhood Acute Lymphoblastic Leukemia

Chemotherapy of Childhood Acute Lymphoblastic Leukemia

Assay of azathioprine, 6‐mercaptopurine and a novel thiopurine metabolite in human plasma.

Thiopurine methyltransferase: a review and a clinical pilot study

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