Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics of Methotrexate in Children

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Among the few antineoplaslic agents investigated pharmacologically in children and adults, methotrexate has been clearly demonstrated to be handled differently in the two age groups. Age has in fact proved to be a major determinant, exerting an effect on both the pharmacokinetics and pharmacodynamics of methotrexate. Its pharmacokinetics, in turn, determine the drug toxicity. The β-phase of methotrexate clearance, represented by the plasma drug concentration 48 hours from the start of a 6-hour infusion in a high dose treatment regimen, appears to be constant with age. In children, an increasing plasma drug concentration is apparent with increasing age, but whether this trend reflects a potential increase in the area under the plasma concentration-time curve of methotrexate has yet to be defined.

Recent investigations have suggested that the drug is more completely distributed in the tissues of children than adults at the same infused dosage. This may explain the increased tissue toxicity caused by methotrexate. However, other observations suggest a faster drug turnover rate in the tissues of children. This may prevent the drug from concentrating in vital organs. Whether the metabolism of methotrexate, particularly the biosynthesis of methotrexate polyglutamates, plays a role in the biological effect of the drug is worthy of further investigation.

The high brain tissue concentration after systemic methotrexate infusion and the slower efflux of methotrexate from brain tissues and cerebrospinal fluid make these tissues vulnerable to methotrexate toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abelson, H.T.; Fosburg, M.T.; Beardsley, G.P.; Goorin, A.M.; Gorka, C.; Link, M. and Link, D.: Methotrexate-induced renal impairment: Clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. Journal of Clinical Oncology 1: 208–216 (1983).

    PubMed  CAS  Google Scholar 

  • Aherne, G.W.; Piall, E.M. and Marks, V.: Development and applications of a radioimmunoassay for methotrexate. British Journal of Cancer 36: 608–617 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Balis, F.M.; Savitch, J.L. and Bleyer, W.A.: Pharmacokinetics of oral methotrexate in children. Cancer Research 43: 2342–2345 (1983).

    PubMed  CAS  Google Scholar 

  • Bergermeyer, H.U.: Principles of Enzymatic Analysis, pp.796–797 (Verlag Chemie, Weinheim 1978).

    Google Scholar 

  • Bertino, J.R.: Clinical pharmacology of methotrexate. Medical and Pediatric Oncology 10: 401–411 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Bleyer, W.A.: The clinical pharmacology of methotrexate: New applications of an old drug. Cancer 41: 36–51 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Bratlid, D. and Moe, P.J.: Pharmacokinetics of high-dose methotrexate treatment in children. European Journal of Clinical Pharmacology 14: 143–147 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Brown, L.F.; Johnson, G.F.; White, D.L. and Feld, R.D.: Enzyme inhibition assay for methotrexate with a discrete analysis, the ABA-100. Clinical Chemistry 26: 335–338 (1980).

    PubMed  CAS  Google Scholar 

  • Calvert, A.H. and Turabull, C.P. (Eds): Proceedings of the International Symposium on Methotrexate. Cancer Treatment Reports 65 (Suppl. 1): 1–189 (1981).

    PubMed  Google Scholar 

  • Chan, K.K.; Balachandran Nayar, M.S.; Cohen, J.L.; Chlebowski, R.T.; Liebman, H.; Stolinsky, D. and Farquhar, D.: Metabolism of methotrexate in mass after high and conventional doses. Research Communications in Chemical Pathology and Pharmacology 28: 551–561 (1980).

    PubMed  CAS  Google Scholar 

  • Chard, R.J.; Smith, E.K. and Hartman, J.R.: Metabolic studies of prednisone in previously untreated acute leukemia of childhood. Proceedings of the American Association of Cancer Research 49: 13 (1966).

    Google Scholar 

  • Craft, A.W.; Rankin, A. and Aheme, W.: Methotrexate absorption in children with acute lymphoblastic leukemia. Cancer Treatment Reports 65 (Suppl. 1): 77–81 (1981).

    PubMed  Google Scholar 

  • Donehower, R.C.; Hande, K.R.; Drake, J.C. and Chabner, B.A.: Presence of 2,4-diamino-N10-methylpteroic and after high-dose methotrexate. Clinical Pharmacology and Therapeutics 26: 63–72 (1979).

    PubMed  CAS  Google Scholar 

  • Evans, W.E. and Rivera, G.: Pharmacokinetic evaluation of high dose oral methotrexate in children with acute lymphocytic leukemia. Proceedings of the American Association of Cancer Research 20: 266 (1979).

    Google Scholar 

  • Finkelstein, J.Z.; Schern, J. and Karon, M.: Pharmacologic studies of tritiated cytosine arabinoside (NSC-63878) in children. Cancer Chemotherapy Reports 54: 35–39 (1970).

    Google Scholar 

  • Finley, P.R.; Williams, R.J.; Griffith, F. and Lichiti, D.A.: Adaptation of the enzyme-multiplied immunoassay for methotrexate to the centrifugal analyses. Clinical Chemistry 26: 341–343 (1980).

    PubMed  CAS  Google Scholar 

  • Fountain, J.R.; Hutchison, D.J.; Waring, G.B. and Burchenal, J.H.: Persistence of amethopterin in normal mouse tissues. Proceedings of the Society for Experimental Biology and Medicine 83: 369–372 (1953).

    PubMed  CAS  Google Scholar 

  • Frankel, L.S.; Wang, Y.M.; Pullen, J.; Nitschke, R. and Doering, E.J.: High dose intravenous methotrexate with an intrathecal methotrexate boost in the maintenance of acute lymphocytic leukemia in children. (Abstract.) Proceedings of the American Association for Cancer Research 21: 389 (1980).

    Google Scholar 

  • Freeman-Narrod, M.: The pharmacology of methotrexate; in Porter and Wiltshaw (Eds) Methotrexate in the Treatment of Cancer, pp. 17–21 (Williams and Wilkins, Baltimore 1962).

    Google Scholar 

  • Freeman-Narrod, M.; Gerstley, B.J.; Engstrom, P.F. and Bornstein, R.S.: Comparison of serum concentrations of methotrexate after various routes of administration. Cancer 36: 1619–1624 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Fujimoto, T. and Sasaki, K.: Pharmacokinetics of high-dose methotrexate in serum and cerebrospinal fluid. (In Japanese) Gan To Kagaku Ryoho 6 (Suppl. 12): 279–286 (1979).

    Google Scholar 

  • Fujimoto, T.; Hasegawa, K.; Take, H.; Miyazaki, S.; Kishida, K.; Shin, H. and Goya, N.: Maintenance therapy and pharmacokinetics of intermittent high-dose methotrexate in acute childhood leukemia. Acta Haematologica Japonica 40: 119–132 (1977).

    PubMed  CAS  Google Scholar 

  • Goh, T.S.; Wong, K.Y.; Lampkin, B.; O’Leary, J. and Gnarra, D.: Evaluation of 24-hour infusion of high-dose methotrexate — Pharmacokinetics and toxicity. Cancer Chemotherapy and Pharmacology 3: 177–180 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Grossie, V.B.; Ho, D.H.W. and Loo, T.L.: Effect of malnutrition on methotrexate toxicity and tissue levels of dihydrofolate reductase in the rat. Cancer Treatment Reports 66: 85–89 (1982).

    PubMed  CAS  Google Scholar 

  • Hande, K.; Gover, J. and Fletcher, R.: Trimethoprim interferes with serum methotrexate assay by the competitive protein binding technique. Clinical Chemistry 26: 1617–1619 (1980).

    PubMed  CAS  Google Scholar 

  • Higgins, G.B.; Shore, N.A.; Eteubanas, E.; Mompartner, R.L.; Jamin, D. and Rucker, N.: Dianhydrogalactitol: Phase I clinical pharmacological studies in childhood cancer. Proceedings of the American Association for Cancer Research 17: 165 (1976).

    Google Scholar 

  • Hignite, C.E.; Shen, D.D. and Azarnoff, D.L.: Separation and identification of impurities in parenteral methotrexate dosage form. Cancer Treatment Reports 62: 13–18 (1978).

    PubMed  CAS  Google Scholar 

  • Hosoya, R.; Sasaki, K.; Fujimoto, T.; Wang, Y.M. and Sutow, W.W.: High-dose methotrexate with citrovorum factor rescue therapy: Measurement of methotrexate and its metabolite using high pressure liquid chromatography and the clinical significance. (In Japanese.) Cancer and Chemotherapy 8: 1325–1344 (1981).

    Google Scholar 

  • Howell, S.K.; Wang, Y.M.; Hosoya, R. and Sutow, W.W.: Plasma methotrexate as determined by liquid chromatography, enzyme-inhibition assay, and radioimmunoassay after high-dose infusion. Clinical Chemistry 26: 734–739 (1980).

    PubMed  CAS  Google Scholar 

  • Huffman, D.H.; Wan, S.H.; Azarnoff, D.L. and Hoogstraten, B.: Pharmacokinetics of methotrexate. Clinical Pharmacology and Therapeutics 14: 572–579 (1973).

    PubMed  CAS  Google Scholar 

  • Isacoff, W.H.; Morrison, P.F.; Aroesty, J.; Wills, K.L.; Block, J.B. and Lincoln, T.L.: Pharmacokinetics of high dose methotrexate with citrovorum factor rescue. Cancer Treatment Reports 61: 1665–1674 (1977).

    PubMed  CAS  Google Scholar 

  • Jacobs, S.A.; Stoller, R.G.; Chabner, B.A. and Johns, D.G.: 7-Hydroxy-methotrexate as a urinary metabolite in human subjects and Rhesus monkeys receiving high-dose methotrexate. Journal of Clinical Investigation 57: 534–538 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Jacobs, S.A.; Stoller, R.G.; Chabner, B.A. and Johns, D.G: Dose-dependent metabolism of methotrexate in man and Rhesus monkeys. Cancer Treatment Reports 61: 651–656 (1977).

    PubMed  CAS  Google Scholar 

  • Jaffe, N.; Prudich, J.; Knapp, J.; Wang, Y.M.; Bowman, R.; Cangir, A.; Ayala, A.; Chuang, V. and Wallace, S.: Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. Journal of Clinical Oncology 1: 428–431 (1983).

    PubMed  CAS  Google Scholar 

  • Jolivet, J. and Schilsky, R.L.: High pressure liquid chromatography analysis of methotrexate polyglutamates in cultured human breast cancer cells. Biochemical Pharmacology 30: 1387–1390 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Kamen, B.A.; Holcenberg, J.S.; Turo, K. and Whitehead, V.M.: Variability of red blood cell folate and methotrexate in children with acute lymphocytic leukemia. (Abstract.) Proceedings of the American Association for Cancer Research 24: 135 (1983).

    Google Scholar 

  • Krakower, G.R.; Nylen, P.A. and Kamen, B.A.: Separation and identification of subpicomole amounts of methotrexate polyglutamatc in animals and human biopsy materials. Analytical Biochemistry 122: 412–416 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Kearney, P.J.; Light, P.A.; Preece, A. and Mott, M.G.: Unpredictable serum levels after oral methotrexate in children with acute lymphoblastic leukaemia. Cancer Chemotherapy and Pharmacology 3: 117–120 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Kinkade Jr, J.M.; Vogler, W.R. and Dayton, P.G.: Plasma level of methotrexate in cancer patients as studied by an improved spectrofluorometric method. Biochemical Medicine 10: 337–347 (1974).

    Article  PubMed  Google Scholar 

  • Lankelma, J.; van der Kleijn, E. and Termond, E.F.S.: Assay of methotrexate and 7-hydroxymethotrexate by high pressure liquid chromatography and its application to clinical pharmacokinetics; in Pinedo (Ed.) Clinical Pharmacology of Anti-Neoplastic Agents, pp. 13–28 (Elsevier/North-Holland Biomedical Press, Amsterdam 1978).

    Google Scholar 

  • Liegler, D.M., Henderson, E.S.; Hahn, M.A. and Oliverio, V.: The effect of organic acids on renal clearance of methotrexate in man. Clinical Pharmacology and Therapeutics 10: 849–857 (1969).

    PubMed  CAS  Google Scholar 

  • Loo, T.L.; Luce, J.K.; Sullivan, M.P. and Frei, E. III: Clinical pharmacologic observations on 6-mercaptopurine and 6-methyl thiopurine ribonucleoside. Clinical Pharmacology and Therapeutics 9: 180–194 (1968).

    PubMed  CAS  Google Scholar 

  • Matthias, M.: Cytostatic therapy of malignant neoplasms: I. Introduction and prerequisites of tumorchemotherapy for pharmacokinetic and cell biological viewpoints. (In German) Deutsch Gesundheitswesen 34: 1009–1017 (1979).

    Google Scholar 

  • Mihranian, M.; Daly, J.; Wang, Y.M.; Copeland, E. and Dudrick, S.: Methotrexate pharmacokinetics: Effect of protein depletion and repletion. (Abstract.) Federation Proceedings 41: 281 (1982).

    Google Scholar 

  • Parker, D.; Bate, C.M.; Craft, A.W.; Graham-Pole, J.; Malpas, J.S. and Stansfeld, A.G.: Liver damage in children with acute leukemia and non-Hodgkin’s lymphoma on oral maintenance chemotherapy. Cancer Chemotherapy and Pharmacology 4: 121–127 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Perez, C.; Wang, Y.M.; Sutow, W.W. and Herson, J.: Significance of the 48-hour plasma level in high-dose methotrexate regimens. Cancer Clinical Trials 1: 107–111 (1978).

    PubMed  CAS  Google Scholar 

  • Perez, C.; Sutow, W.W.; Wang, Y.M. and Herson, J.: Evaluation of overall toxicity of high dosage methotrexate regimens. Medical Pediatrics and Oncology 6: 219–228 (1979).

    Article  CAS  Google Scholar 

  • Pinkerton, C.R.; Welshman, S.G.; Dempsey, S.I.; Bridges, J.M. and Glasgow, J.F.T.: Absorption of methotrexate under standardized conditions in children with acute lymphoblastic leukaemia. British Journal of Cancer 42: 613–615 (1980a).

    Article  PubMed  CAS  Google Scholar 

  • Pinkerton, C.R.; Glasgow, J.F.T.; Welshman, S.G. and Bridges, J.M.: Can food influence the absorption of methotrexate in children with acute lymphoblastic leukaemia? Lancet 2: 944–945 (1980b).

    Article  PubMed  CAS  Google Scholar 

  • Pitman, S.W.; Parker, L.M.; Tattersall, M.H.N.; Jaffe, N. and Frei, E. III.: Clinical trial of high dose methotrexate (NSC-740) with citrovorum factor (NSC-3590) toxicologic and therapeutic observations. Cancer Chemotherapy Reports 6 (part 3): 43–49 (1975).

    Google Scholar 

  • Poser, R.G.; Sirotnak, F. and Chello, P.L.: Extracellular recovery of methotrexate-polyglutamate following efflux from L1210 leukemia cells. Biochemical Pharmacology 29: 2701–2704 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Poser, R.G.; Sirotnak, F.M. and Chello, P.L.: Differential synthesis of methotrexate polyglutamates in normal proliferative and neoplastic mouse tissue in vivo. Cancer Research 41: 4441–4446 (1981).

    PubMed  CAS  Google Scholar 

  • Pratt, C.B.; Ransom, J.L. and Evans, W.E.: Age-related adriamycin cardiotoxicity in children. Cancer Treatment Reports 62: 1381–1385 (1978).

    PubMed  CAS  Google Scholar 

  • Ramirez, I.; Sullivan, M.P.; Wang, Y.M.; Martin, R.G. and Butler, J.J.: Effective therapy for Burkitt’s lymphoma; high-dose cyclophosphamide — high-dose methotrexate with coordinated intrathecal therapy, plasma and cerebrospinal fluid methotrexate levels. Cancer Chemotherapy and Pharmacology 3: 103–109 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Rane, A. and Wilson, J.T.: Clinical pharmacokinetics in infants and children. Clinical Pharmacokinetics 1: 2–24 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Raso, V. and Schreiber, R.: A rapid and specific radioimmunoassay for methotrexate. Cancer Research 35: 1407–1410 (1975).

    PubMed  CAS  Google Scholar 

  • Redetzki, H.M.; Redetzki, J.E. and Elias, A.L.: Resistance of the rabbit to methotrexate isolation of a drug metabolite with decreased cytotoxicity. Biochemical Pharmacology 15: 425–433 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Ritschel, W.A.: Handbook of Basic Pharmacokinetics. (Drug Intelligence Publications, Hamilton 1980).

    Google Scholar 

  • Roberts, D.: An isotopic assay for dihydrofolate reductase. Biochemistry 5: 3549–3551 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Sasaki, K.; Hosoya, R.; Wang, Y.M. and Raulston, G.L.: 7-Hydroxy-methotrexate in rabbits. Biochemical Pharmacology 32: 503–507 (1983).

    Article  PubMed  CAS  Google Scholar 

  • Shapiro, W.R.; Allen, J.C. and Metha, B.: Pharmacodynamics of entry of methotrexate into brain of humans, monkeys and a rat brain tumor model; in Paoletti el al. (Eds) Multidisciplinary Aspects of Brain Tumor Therapy, pp. 135–142 (Elsevier/North-Holland Biomedical Press, Amsterdam 1979).

    Google Scholar 

  • Smith, D.K.; Omura, G.A. and Ostroy, F.: Clinical pharmacology of intermediate-dose oral methotrexate. Cancer Chemotherapy and Pharmacology 4: 117–120 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Sommadossi, J.P.; Aubert, C.; Cano, J.P.; Rigault, J.P. and Monjanel, S.: The advantage and limitations of posology rationalization. Therapie 35: 391–393 (1980).

    PubMed  CAS  Google Scholar 

  • Spector, G.B.; Wang, Y.M.; Gleiser, C.A.; Chan, R.C. and van Eys, J.: Effect of gentamicin and irradiation on the toxicity of high-dose methotrexate in rats. Cancer Treatment Reports 64: 989–991 (1980).

    PubMed  CAS  Google Scholar 

  • Spreafico, F. and Rossi, M.S.: Antineoplastic agents; in Morselli (Ed.) Drug Disposition During Development, pp. 101–122 (Spectrum Publication, New York 1977).

    Google Scholar 

  • Stoller, R.G.; Jacobs, S.A.; Drake, J.C.; Lutz, R.J. and Chabner, B.A.: Pharmacokinetics of high-dose methotrexate (NSC-740). Cancer Treatment Repons 6 (part 3): 19–24 (1975).

    Google Scholar 

  • Stoller, R.G.; Hande, K.R.; Jacobs, S.A.; Rosenberg, S.A. and Chabner, B.A.: Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. New England Journal of Medicine 297: 630–634 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Sutow, W.W.: in Malignant Solid Tumors in Children. A Review, p.228 (Raven Press, New York 1981).

    Google Scholar 

  • Szeto, D.W.; Cheng, Y.C.; Rosowsky, A.; Yu, S.C.; Medest, E.J.; Pipier, J.R.; Temple Jr, C.; Elliott, R.D.; Rose, J.D. and Montgomery, J.A.: Human thymidylate synthetase III effects of methotrexate and folate analogs. Biochemical Pharmacology 28: 2633–2637 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Tan, C.: Clinical and pharmacokinetic studies of vindesine in 50 children with malignant diseases in current chemotherapy. Proceedings of the 10th International Congress on Chemotherapy, International Society of Chemotherapy, Vol. 2 (1978).

    Google Scholar 

  • Valerino, D.M.; Johns, D.G.; Zaharko, D.S. and Oliverio, V.T.: Studies of the metabolism of methotrexate by intestinal flora. Biochemical Pharmacology 21: 821–831 (1972).

    Article  PubMed  CAS  Google Scholar 

  • van Eys, J. (Ed.): Methotrexate. Cancer Bulletin 33: 37–77 (1981).

    Google Scholar 

  • van Eys, J. and Wang, Y.M.: Minimal toxicity and anomalous drug kinetics in a patient receiving high dose methotrexate. Cancer Bulletin 34: 120–122 (1982).

    Google Scholar 

  • von Hoff, D.D.; Penta, J.S.; Helman, L.J. and Slavik, M.: Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration. Cancer Treatment Reports 61: 745–748 (1977).

    Google Scholar 

  • Wang, Y.M.: Observations on the clinical pharmacology of high-dose methotrexate in children. Cancer Bulletin 30: 181–184 (1978).

    Google Scholar 

  • Wang, Y.M.: Contribution of clinical pharmacology in the treatment of childhood cancer. (In Japanese.) Cancer and Chemotherapy 8: 64–72 (1981).

    CAS  Google Scholar 

  • Wang, Y.M.; Howell, S.K. and Benvenuto, J.A.: Paired-ion high pressure liquid chromatography of methotrexate and metabolites in biological fluids. Journal of Liquid Chromatography 3: 1071–1078 (1980).

    Article  CAS  Google Scholar 

  • Wang, Y.M.; Kim, P.-Y.; Lantin, E.; van Eys, D.C.; Romsdahl, M.M. and Sutow, W.W.: Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion. Medical and Pediatric Oncology 4: 221–229 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Wang, Y.M.; Lantin, E. and Sutow, W.W.: Methotrexate in blood, urine and cerebrospinal fluid of children receiving high-dose by infusion. Clinical Chemistry 22: 1053–1056 (1976a).

    PubMed  CAS  Google Scholar 

  • Wang, Y.M.; Kim, P.Y.; van Eys, D.C. and Sutow, W.W.: Study of contaminants and metabolites during therapy with high dose of methotrexate. Clinical Chemistry 22: 1937 (1976b).

    PubMed  CAS  Google Scholar 

  • Wang, Y.M. and Loo, T.L.: Mechanism of action of methotrexate: contributions of molecular, cellular and clinical pharmacology. Cancer Bulletin 33: 49–54 (1981).

    Google Scholar 

  • Wang, Y.M.; Sutow, W.W.; Romsdahl, M.M. and Perez, C.: Age related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma. Cancer Treatment Reports 63: 405–410 (1979).

    PubMed  CAS  Google Scholar 

  • Watson, E.; Cohen, J.L. and Chan, K.K.: High pressure liquid Chromatographic determination of methotrexate and its major metabolite. 7-hydroxymethotrexate, in human plasma. Cancer Treatment Reports 62: 381–387 (1978).

    PubMed  CAS  Google Scholar 

  • White, J.C.: Reversal of methotrexate binding to dihydrofolate reductase by dihydrofolate. Journal of Biological Chemistry 254: 10889–10895 (1979).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Pediatrics, The University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, Texas, 77030, USA

    Y.-M. Wang & T. Fujimoto

  2. Department of Pediatrics, Aichi Medical University, Aichi-ken, Nagoya, Japan

    Y.-M. Wang & T. Fujimoto

Authors
  1. Y.-M. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, YM., Fujimoto, T. Clinical Pharmacokinetics of Methotrexate in Children. Clin Pharmacokinet 9, 335–348 (1984). https://doi.org/10.2165/00003088-198409040-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-198409040-00003

Keywords

Search

Navigation