Fluorometric high-performance liquid chromatographic analysis of 10-deazaaminopterin, 10-ethyl-10-deazaaminopterin, and known metabolites

Kinahan, James J.; Samuels, Lawrence L.; Farag, Fouad; Fanucchi, Michael; Vidal, Pedro; Sirotnak, Francis M.; Young, Charles W.

doi:10.1016/0003-2697(85)90460-9

Cited by 11 publications

(4 citation statements)

References 18 publications

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“…23 This assay was validated with pralatrexate. Plasma samples were analyzed for pralatrexate concentration using a sensitive dihydrofolate reductase base assay similar to that used for the quantitation of methotrexate.…”

Section: Methodsmentioning

confidence: 99%

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A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients With Relapsed or Refractory Non-Hodgkin's or Hodgkin's Lymphoma

Mould

Sweeney

Duffull

et al. 2009

Clin Pharmacol Ther

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In a pralatrexate phase I study, patients displayed a high incidence of mucositis of grades 3 and 4. Preliminary evaluations of the pharmacokinetics of the drug and its association with mucositis suggested that pralatrexate exposure (area under the concentration-time curve (AUC)) could be controlled with body size (e.g., weight or body surface area)-based dosing and that pretreatment with folic acid and vitamin B(12) might diminish the incidence and severity of mucositis. The study was amended, with revised dosing and vitamin B(12) administration. Data from 47 patients were evaluated using NONMEM. Weight and methylmalonic acid (MMA) level were predictive of pharmacokinetic (PK) variability. AUC and MMA level were positively correlated with the risk of developing mucositis. A lower AUC schedule with vitamin B(12) pretreatment may control mucositis without compromising efficacy. The covariates identified in this study are comparable with other antifolate analogs. The application of modeling was a critical step in the development of pralatrexate, yielding important suggestions for dose, scheduling, and pretreatment modifications.

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Section: Methodsmentioning

confidence: 99%

“…Plasma samples were analyzed for pralatrexate concentration using a sensitive dihydrofolate reductase base assay similar to that used for the quantitation of methotrexate. 23 This assay was validated with pralatrexate. The lower limit of detection was 0.5 ng/ml, with low interday variability.…”

Section: Methodsmentioning

confidence: 99%

A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients With Relapsed or Refractory Non-Hodgkin's or Hodgkin's Lymphoma

Mould

Sweeney

Duffull

et al. 2009

Clin Pharmacol Ther

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“…The fluorometric high-performance liquid chromatographic assay [29,30] takes advantage of the high native fluorescence exhibited by pteridinecontaining compounds which have carbon in the 10 position. This technique was shown to be suitable for analysis of 10-EdAM, its analogs, and polyglutamyl derivatives in plasma, urine and tissue.…”

Section: Lo-ethyl-lo-deazaaminopterinmentioning

confidence: 99%

“…Kinahan et al [36] report preliminary toxicology findings and pharmacokinetics for 10-EdAM. The terminal plasma half-life in dogs is 9 hours.…”

Section: Lo-ethyl-lo-deazaaminopterinmentioning

confidence: 99%

Biological and biochemical properties of new anticancer folate antagonists

Fry¹,

Jackson²

1987

Cancer Metast Rev

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We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTXinsensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.

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Synthesis of the 7-Hydroxy Metabolites of Methotrexate and 10-Ethyl-10-Deazaaminopterin

Dawson

Okrongly

Hobbs

et al. 1987

Journal of Pharmaceutical Sciences

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Fluorometric high-performance liquid chromatographic analysis of 10-deazaaminopterin, 10-ethyl-10-deazaaminopterin, and known metabolites

Cited by 11 publications

References 18 publications

A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients With Relapsed or Refractory Non-Hodgkin's or Hodgkin's Lymphoma

A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients With Relapsed or Refractory Non-Hodgkin's or Hodgkin's Lymphoma

Biological and biochemical properties of new anticancer folate antagonists

Synthesis of the 7-Hydroxy Metabolites of Methotrexate and 10-Ethyl-10-Deazaaminopterin

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