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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics and Metabolism of the Methotrexate Metabolite 2,4-Diamino-N 10-methylpteroic Acid

Brigitte C. Widemann, Edward Sung, Lawrence Anderson, Wanda L. Salzer, Frank M. Balis, Karen S. Monitjo, Cynthia McCully, Mary Hawkins and Peter C. Adamson
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 894-901;
Brigitte C. Widemann
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Edward Sung
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Lawrence Anderson
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Wanda L. Salzer
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Frank M. Balis
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Karen S. Monitjo
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Cynthia McCully
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Mary Hawkins
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Peter C. Adamson
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Abstract

The novel methotrexate (MTX) rescue agent carboxypeptidase-G2 (CPDG2) converts >98% of plasma MTX to 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is eliminated more rapidly than MTX in these patients, suggesting nonrenal elimination. The pharmacokinetics and metabolism of DAMPA were studied in four nonhuman primates with reverse-phase HPLC with UV, photodiode array detection, and mass spectroscopy. The mean peak plasma DAMPA concentration was 51 μM and the plasma disposition was described by a three-compartment open model with first order elimination. The mean clearance of DAMPA was 1.9 l/kg/h and the mean terminal half-life was 51 min. Forty-six percent of the dose was excreted in the urine as parent compound. Three DAMPA metabolites, hydroxy-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide, were identified in plasma and urine. These metabolites also were identified in plasma from patients who received CPDG2 as an MTX rescue agent. The cytotoxicity of DAMPA and its effect on MTX cytotoxicity were assessed in the Molt-4 human leukemic cell line. DAMPA was not cytotoxic and did not significantly alter the cytotoxicity of MTX. In nonhuman primates metabolism of DAMPA is a major route of DAMPA elimination, and metabolism underlies the more rapid elimination of DAMPA versus MTX in patients with MTX-induced renal dysfunction after administration of CPDG2.

Footnotes

  • Send reprint requests to: Brigitte C. Widemann, M.D., Pediatric Oncology Branch, National Cancer Institute, Bldg. 10, Room 13N240, 10 Center Dr., Bethesda, MD 20892-1928. E-mail:bw42y{at}nih.gov

  • ↵1 Current address: Keesler Air Force Base, Biloxi, MS, 81st MDOS/SGOC 301 Fisher St., Room 1A132.

  • ↵2 Current address: Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Suite 902, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318.

  • Abbreviations:
    HDMTX
    high-dose methotrexate
    MTX
    methotrexate
    CPDG2
    carboxypeptidase-G2
    DAMPA
    2,4-diamino-N10-methylpteroic acid
    PDA
    photodiode array detection
    7-OH-MTX
    7-hydroxy-methotrexate
    AO
    aldehyde oxidase
    MS
    mass spectroscopy
    OH-DAMPA
    hydroxy-DAMPA
    DAMPA-glc
    DAMPA-glucuronide
    OH-DAMPA-glc
    hydroxy-DAMPA-glucuronide
    • Received January 3, 2000.
    • Accepted May 11, 2000.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics and Metabolism of the Methotrexate Metabolite 2,4-Diamino-N 10-methylpteroic Acid

Brigitte C. Widemann, Edward Sung, Lawrence Anderson, Wanda L. Salzer, Frank M. Balis, Karen S. Monitjo, Cynthia McCully, Mary Hawkins and Peter C. Adamson
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 894-901;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics and Metabolism of the Methotrexate Metabolite 2,4-Diamino-N 10-methylpteroic Acid

Brigitte C. Widemann, Edward Sung, Lawrence Anderson, Wanda L. Salzer, Frank M. Balis, Karen S. Monitjo, Cynthia McCully, Mary Hawkins and Peter C. Adamson
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 894-901;
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