Detection by high-performance liquid chromatography of methotrexate and its metabolites in tumor tissue from osteosarcoma patients treated with high-dose methotrexate/leucovorin rescue

Samuels, Lawrence L.; Feinberg, Aaron; Moccio, D. M.; Sirotnak, Francis M.; Rosen, Gerald

doi:10.1016/0006-2952(84)90685-3

Cited by 23 publications

(3 citation statements)

References 15 publications

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“…Similar methodology has been used to measure the polyglutamated forms of methotrexate in isolated human leukaemic blast cells (Goker et al, 1993). Methotrexate polyglutamates have been determined in human tissue samples after high-dose therapy by using HPLC with subsequent detection in fractions using radioimmunoassay (Anzai et al, 1987) or by using the radioligand binding assay (Samuels et al, 1984). Total methotrexate has also been measured by radioimmunoassay as a measure of polyglutamation in erythrocytes from patient treated with high-dose therapy (Schalhom et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Aherne

Ward²,

Lawrence³

et al. 1998

Br J Cancer

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Summary ZD1 694 (Tomudex, raltitrexed) is a specific quinazoline antifolate thymidylate synthase inhibitor that relies on polyglutamation for high potency. Antibodies to ZD1694 have been used to establish a sensitive radioimmunoassay as an alternative to high-performance liquid chromatography (HPLC). The radioimmunoassay is reproducible, accurate and provides a means of determining low levels of ZD1694 in plasma (< 1 nM). By virtue of the high cross-reactivity of the antibodies with polyglutamated forms of ZD1 694, it is also possible to measure the total concentration of drug in tissues. Results obtained in L1210 mouse leukaemia cells and in mouse tissues were similar to those previously determined using radiolabelled drug. Pharmacokinetic studies in mice have confirmed that the compound is rapidly eliminated from the plasma and that there is a prolonged terminal elimination phase. ZD1694 was measured in plasma (0.56 ng ml-1; 1.2 pmol ml-') up to 7 days after a single i.p. dose of 100 mg kg-' ZD1 694. Liver, kidney and gut epithelium had a substantially higher level of ZD1 694 immunoreactivity than plasma. For example, 24 h after a single i.p. dose at 1, 10 and 100 mg kg-', total drug levels in the liver were 480, 325 and 152 times higher than plasma levels respectively. In kidney and gut epithelium, total drug levels at these doses were approximately 55 and 34 times those of plasma. The high tissue to plasma ratios were maintained for at least 7 days after administration. Similarly, high tissue to plasma ratios (> 100) were found in dogs treated with a clinically relevant dose of ZD1 694. These were maintained for 4 weeks in liver and kidney tissue (> 100). Total gastrointestinal concentrations of ZD1694 were approximately 10 times higher than plasma 3 days after administration, but levels were near to the limit of detection at 4 weeks. These results are consistent with extensive polyglutamation of ZD1 694 within tissues in both mice and dog and provide further support for the infrequent schedule that has been used clinically. Although it has not been possible to measure individual polyglutamated forms of ZD1 694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD1 694.

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Section: Discussionmentioning

confidence: 99%

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Aherne

Ward²,

Lawrence³

et al. 1998

Br J Cancer

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“…Cancer cells, including several leukaemia subsets, differ in their sensitivity to MTX due to differences in their influx and efflux of MTX, in their DHFR expression, and in their propensity for MTX polyglutamation. However, the clinical impact of variation in MTX‐polyglutamation may be weak, since even a 300‐fold increase in MTX doses may lead to only a 2·0‐ to 2·5‐fold difference in intracellular MTX content 1 d after the drug has been administered (Samuels et al , 1984; Winick et al , 1987). Furthermore, not only peak concentrations but also exposure time and the dose of Leukovorin rescue is of importance.…”

Section: Mtx Chemosensitivity Of Cancersmentioning

confidence: 99%

Advances in individual prediction of methotrexate toxicity: a review

2009

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SummaryAs the cure rates for haematological malignancies have improved, the exploration of the balance between efficacy and side effects has become a major research target. The antifolate methotrexate is widely used in the treatment of acute lymphoblastic leukaemia, non-Hodgkin lymphoma, and osteosarcoma. Even when given identical methotrexate doses, patients vary significantly in their response and pattern of toxicities. This diversity can, to some extent, be linked to sequence variations in genes involved in drug absorption, metabolism, excretion, cellular transport, and effector targets or target pathways. In the coming years pharmacogenomics is expected to change our approaches to individualised therapy with methotrexate. However, genetic polymorphisms affect the pharmacokinetics and dynamics of all the drugs a patient receive as well as the normal tissues tolerance to a given drug exposure. Thus, although high-throughput techniques will allow mapping of tens of thousands of genetic polymorphisms in one run, it will be a major challenge to dissect out which of these have the strongest impact on efficacy and toxicity and hence should be the targets for intervention. This paper discusses the pharmacology of methotrexate and reviews studies on haematological malignancies that have attempted to predict the risk of toxicity by specific clinical or genetic features.

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“…MTX and 7-OH-MTX taken up by cells is metabolized to MTX polyglutamates (MTX-PGs) by folylpoly-γ-glutamate synthetase in various cells, including tumor samples obtained from patients and normal human cells [154,155]. For example, normal myeloid precursor cells converted MTX to MTX-PGs in a concentration- and time-dependent manner, preferentially retaining MTX-PGs with three to seven glutamyl moieties.…”

Section: Introduction For Methotrexatementioning

confidence: 99%

Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

Murakami

Mori

2012

Pharmaceuticals

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Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX) is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.

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Detection by high-performance liquid chromatography of methotrexate and its metabolites in tumor tissue from osteosarcoma patients treated with high-dose methotrexate/leucovorin rescue

Cited by 23 publications

References 15 publications

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Advances in individual prediction of methotrexate toxicity: a review

Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

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