Summary
Serum methotrexate (MTX) levels were measured in 20 patients who received an oral, intermediatedose MTX regimen preceded by an IV loading dose, with or without probenecid. Plateau serum MTX levels were relatively modest (≤2x10-6 M) during the 24 h of treatment. Pretreatment with probenecid (PBC) led to a doubling of the serum MTX level and a significant increase in the area under the concentration-time curve. Nevertheless, oral therapy is not a suitable means of producing sustained, high (10-5 molar) MTX levels, even with the addition of PBC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aherne GW, Piall E, Marks V, Mould G, White WF (1978) Prolongation and enhancement of serum methotrexate concentrations by probenecid. Br Med J 1: 1097
Bender RA (1975) Membrane transport of methotrexate (NSC 740) in human neoplastic cells. Cancer Chemother Rep 6: 73
Fry DW, Yalowich JC, Goldman ID (1982) Augmentation of the intracellular levels of polyglutamyl derivatives of methotrexate by vincristine and probenecid in Ehrlich ascites tumor cells. Cancer Res 42: 2532
Gibaldi M (1977) Biopharmaceutics and clinical pharmacokinetics, 2nd edn. Lea and Febiger, Philadelphia, p 8
Goldman ID (1974) The mechanism of action of methotrexate: I. Interaction with a low-affinity intracellular site required for maximum inhibition of deoxyribonucleic acid synthesis in L-cell mouse fibroblasts. Mol Pharmacol 10: 257
Harvey VJ, Slevin ML, Wollard RC, Johnston A, Barnett MJ, Wrigley PFM, Turner P (1984) The bioavailability of oral intermediate-dose methotrexate: effect of dose subdivision, formulation, and timing in the chemotherapy cycle. Cancer Chemother Pharmacol 13: 91
Howell SB, Olshen RA, Rice JA (1979) Effect of probenecid on cerebrospinal fluid methotrexate kinetics. Clin Pharmacol Ther 26: 641
Israeli ZH, Soliman AM: Cunnigham RF, Plowden JF, Keller JW (1978) The interaction of methotrexate and probenecid in man and dogs. Proc Am Assoc Cancer Res 19: 194
Leighter DG, Henderson ES, Hahn MA, Olverio VT (1979) The effect of organic acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 10: 849
Myers CE, Lippman ME, Elliot HM, Chabner BA (1975) Competitive protein binding assay for methotrexate. Proc Natl Acad Sci USA 72: 3683
Sirotnak FM, Moccio DM, Young CW (1981 a) Increased accumulation of methotrexate by murine tumor cells in vitro in the presence of probenecid which is mediated by preferential inhibition of efflux. Cancer Res 41: 966
Sirotnak FM, Moccio DM, Hancock CH, Young CW (1981 b) Improved methotrexate therapy of murine tumors obtained by probenecid-mediated pharmacological modulation at the level of membrane transport. Cancer Res 41: 3944
Smith DK, Omura GA, Ostroy F, (1980) Clinical pharmacology of intermediate-dose oral methotrexate. Cancer Chemother Pharmacol 4: 117
Wan SH, Huffman DH, Azarnoff DZ, Stephens R, Hoogstraten B (1974) Effect of route of administration and effusions on methotrexate pharmacokinetics. Cancer Res 34: 3487
Author information
Authors and Affiliations
Additional information
Supported in part by grants CA13148 and CA03013 from the National Cancer Institute
Rights and permissions
About this article
Cite this article
Lilly, M.B., Omura, G.A. Clinical pharmacology of oral intermediate-dose methotrexate with or without probenecid. Cancer Chemother. Pharmacol. 15, 220–222 (1985). https://doi.org/10.1007/BF00263889
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00263889