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Inhibitory effect of bile salts on the enterohepatic circulation of methotrexate in the unanesthetized rat: Inhibition of methotrexate intestinal absorption

  • Original Articles
  • Omtestoma, Methotrexate, Rat, Intestinal Absorption
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Summary

The effect of conjugated and unconjugated bile salts on the intestinal absorption of methotrexate (MTX) in the unanesthetized rat was investigated using a recycling perfusion technique. We initially determined the general characteristics of MTX absorption in vivo. Absorption of low (0.5 μM) and high (6 μM) concentrations of MTX was linear with time for 60 min perfusion and occurred at rates of 0.2 and 1.65 nmol/100 cm dry length/min, respectively. Absorption of 0.5 μM MTX was pH-dependent and increased with decreasing perfusate pH. Absorption of MTX involves two processes: (1) a saturable process with a Kt of 0.98 μM, and (2) a nonsaturable diffusion process. The unconjugated deoxycholate and the conjugated taurocholate inhibited the intestinal absorption of 1 μM MTX in a concentration-dependent manner. The inhibitory effect of bile salts was reversible, and was not due to damage to the intestinal mucosa. The structural analogues folic acid and 5-methyltetrahydrofolate and the organic anions rose bengal and sulfobormophthalein were also inhibitory to MTX absorption. This study demonstrates that a variety of organic anions inhibit MTX intestinal absorption. The possible therapeutic importance of this observation is discussed.

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References

  1. Bleyer WA (1978) The clinical pharmacology of methotrexate. Cancer 41:36–51

    Google Scholar 

  2. Gerwitz DA, Randolph JK, Goldman ID (1980) Potent bile salt and organic anion inhibition of methotrexate in the freshly isolated rat hepatocytes. Cancer Res 40:1852–1857

    Google Scholar 

  3. Hajjar JJ, Khuri RN, Bikhari AB (1975) Effect of bile salts on amino acid transport by rabbit intestine. Am J Physiol 229: 518–523

    Google Scholar 

  4. Henderson GB, Zevely EM (1982) Functional correlations between the methotrexate and general anion transport systems of L-1210 cells. Biochem Interact 4:493–502

    Google Scholar 

  5. Hoffman AF (1976) The enterohepatic circulation of bile acids in man. Clin Gastroenterol 6:3–24

    Google Scholar 

  6. Jolivet J, Cowan KH, Curt GA, et al. (1983) The pharmacology and clinical use of methotrexate. N Engl J Med 309: 1094–1104

    Google Scholar 

  7. Kobayashi Y, Maudsley DV (1970) Practical aspects of double isotope counting. In: Bransome E, Grune S (eds) Liquid scintillation counting. New York, pp 76–85

  8. McManus JFA (1946) Histological demonstration of mucin after periodic acid. Nature 158:202

    Google Scholar 

  9. Russell RM, Dhar J, Dutter SK, et al. (1979) Influence of intraluminal pH on folate absorption: Studies in control subjects and in patients with pancreatic insufficiency. J Lab Clin Invest 93:428–436

    Google Scholar 

  10. Said HM, Hollander D, Strum WB (1984) The inhibitory effect of unconjugated bile acids on the enterohepatic circulation of methotrexate. J Pharm Exp Ther 231:660–664

    Google Scholar 

  11. Shen DD, Azarnoff DL (1978) Clinical pharmacokinetics of amethopterin. Clin Pharmacol 3:1–13

    Google Scholar 

  12. Steinberg SE, Campbell CL, Bleyer CL, et al (1982) Enterohepatic circulation of methotrexate in rats in vivo. Cancer Res 42:1279–1282

    Google Scholar 

  13. Strum WB (1977) A pH-dependent, carrier-mediated transport system for the folate analogue amethopterin in rat jejunum. J Pharmacol Exp Ther 203:640–645

    Google Scholar 

  14. Strum WB (1981) Characteristics of the transport of pteroylglutamate and amethopterin in rat jejunum. J Pharmacol Exp Ther 216:329–333

    Google Scholar 

  15. Strum WB, Leim HH (1977) Hepatic uptake, intracellular protein binding and biliary excretion of amethopterin. Biochem Pharmacol 26:1235–1240

    Google Scholar 

  16. Strum WB, Said HM (1983) Intestinal folate transport. A pH-dependent, carrier-mediated process. In: Blair JA (ed) Chemistry and biology of pteridines. de Gruyter, Berlin New York, pp 1019–1023

    Google Scholar 

  17. Watergaard H, Dietschy J (1974) Delineation of the dimensions of permeability characteristics of the two major diffusion barriers to passive mucosal uptake in the rabbit intestine. J Clin Invest 54:718–732

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology, University of California, 92717, Irvine, CA, USA

    Hamid M. Said & Daniel Hollander

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  1. Hamid M. Said
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  2. Daniel Hollander
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Supported by the U.S. Public Health Service Grant AG 2767

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Said, H.M., Hollander, D. Inhibitory effect of bile salts on the enterohepatic circulation of methotrexate in the unanesthetized rat: Inhibition of methotrexate intestinal absorption. Cancer Chemother. Pharmacol. 16, 121–124 (1986). https://doi.org/10.1007/BF00256160

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  • DOI: https://doi.org/10.1007/BF00256160

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