Skip to main content
SpringerLink
Log in

Concentration andpH dependent steady-state volume of distribution of methotrexate estimated by a simple physiologically based method

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

The effects of plasma concentration and pH on the steady-state volume of distribution, Vss,of methotrexate (MTX) were studied in five conditioned male beagle-mongrel dogs. Steady-state plasma MTX concentrations of approximately 1, 20, and 100μg/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused for the purpose of inducing plasma pH change, while the infusion of an isotonic solution of sodium chloride served as a control. Plasma and urine concentrations of MTX were quantitated by a sensitive high-performance liquid chromatographic method, and the Vss of MTX was estimated by a recently reported physiologically based method of Chiou and Lam. Statistically significant (p<0.05) concentration and plasma pHdependent Vss of MTX were observed. Concentration dependence of Vss was noted in sodium chloride and ammonium chloride infused dogs, but not in bicarbonate treated dogs. There was an average 50.0 and 44.8% increase in Vss at 1 μg/ ml relative to the two higher concentrations (20 and 100 μg/ ml) for dogs treated with ammonium and sodium chloride, respectively. However, Vss of MTX at the targeted concentrations of 20 and 100 μg/ml was relatively constant. Plasma pHdependence of Vss was observed only at the plasma concentration of 1 μg/ml, and on the average, ammonium chloride and sodium chloride treatments resulted in 50.0 and 31.3% higher Vss,respectively, when compared with the bicarbonate treatment. These phenomena appear to be adequately explained by the reported tissue uptake kinetics of MTX.

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

  1. J. Jolivet, K. H. Cowan, G. A. Curt, N. J. Clendeninn, and B. A. Chabner. The pharmacology and clinical use of methotrexate.N. Engl. J. Med. 309:1094–1104 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. D. A. Gewirtz, J. C. White, J. K. Randolph, and I. D. Goldman. Transport, binding, and polyglutamation of methotrexate in freshly isolated rat hepatocytes.Cancer Res. 40:573–578 (1980).

    CAS  PubMed  Google Scholar 

  3. R. L. Schilsky, B. D. Bailey, and B. A. Chabner. Characteristics of membrane transport of methotrexate by cultured human breast cancer cells.Biochem. Pharmacol. 30:1537–1542 (1981).

    Article  CAS  PubMed  Google Scholar 

  4. F. M. Sirotnak, M. G. Sargent, and D. J. Hutchison. Genetically alterable transport of amethopterin in Diplococcus pneumoniae I. Physiological properties and kinetics of the wild-type system.J. Bacteriol. 93:309–314 (1967).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. F. M. Sirotnak, S. Kurita, and D. J. Hutchison. On the nature of a transport alteration determining resistance to amethopterin in the L1210 leukemia.Cancer Res. 28:75–80 (1968).

    CAS  PubMed  Google Scholar 

  6. W. B. Strum. ApH-dependent, carrier-mediated transport system for the folate analog, amethopterin, in rat jejunum.J. Pharmacol. Exp. Ther. 230:640–645 (1977).

    Google Scholar 

  7. R. G. Stoller, S. A. Jacobs, J. C. Drake, R. J. Lutz, and B. A. Chabner. Pharmacokinetics of high-dose methotrexate (NSC-740).Cancer Chemother. Rep. 6:19–24 (1975).

    Google Scholar 

  8. H. Breithaupt and E. Kuenzlen. Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate.Cancer Treat. Rep. 66:1733–1741 (1982).

    CAS  PubMed  Google Scholar 

  9. G. H. Mudge. Agents affecting volume and composition of body fluids. In A. G. Gilman, L. S. Goodman, and A. Gilman (eds.),The Pharmacological Basis of Therapeutics, 6th ed. Macmillan, New York, 1980, p. 868.

    Google Scholar 

  10. W. L. Chiou and G. Lam. Simplified physiologically based method to estimate steady-state volume of distribution.J. Pharm. Sci. 70:967–968 (1981).

    Article  CAS  PubMed  Google Scholar 

  11. C. Y. Lui, M. G. Lee, and W. L. Chiou. UrinarypH and urine flow independent renal clearance of methotrexate in dogs, to be published.

  12. M. G. Lee, M. L. Chen, S. M. Huang, and W. L. Chiou. Pharmacokinetics of drugs in blood I: Unusual distribution of gentamicin.Biopharm. Drug Dispos. 2:89–97 (1981).

    Article  CAS  PubMed  Google Scholar 

  13. M. G. Lee, C. Y. Lui, M. L. Chen, and W. L. Chiou. Pharmacokinetics in blood IV: Unusual distribution, storage effect and metabolism of methotrexate.Int. J. Clin. Pharmacol. Ther. Toxicol 22:530–537 (1984).

    CAS  PubMed  Google Scholar 

  14. M. L. Chen and W. L. Chiou. Clearance studies of methotrexate and 7-hydroxymethotrexate in rabbits after multiple-dose infusion.J. Pharmacokin. Biopharm. 11:515–520 (1983).

    Article  CAS  Google Scholar 

  15. M. L. Chen and W. L. Chiou. Sensitive and rapid high-performance liquid chromatographic method for the simultaneous determination of methotrexate and its metabolites in plasma, saliva and urine.J. chromatogr. Biomed. Appl. 226:125–134 (1981).

    Article  CAS  Google Scholar 

  16. A. Higashi and L. Peters. A rapid colorimetric method for the determination of inulin in plasma and urine.J. Lab. Clin. Med. 35:475–482 (1950).

    CAS  Google Scholar 

  17. M. L. Chen, G. Lam, M. G. Lee, and W. L. Chiou. Arterial and venous blood sampling in pharmacokinetic studies: griseofulvin.J. Pharm. Sci. 71:1386–1389 (1982).

    Article  CAS  PubMed  Google Scholar 

  18. E. S. Henderson, R. H. Adamson, C. Denham, and V. T. Oliverio. The metabolic fate of tritiated methotrexate I. Absorption, excretion and distribution in mice, rats, dogs and monkeys.Cancer Res. 25:1008–1017 (1965).

    CAS  PubMed  Google Scholar 

  19. D. G. Johns, S. Sperti, and S. V. Burgen. The metabolism of tritiated folic acid in man.J. Clin. Invest. 40:1684–1695 (1961).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. G. M. Rubin, T. N. Tozer, and S. Øie. Concentration-dependence of salicylate distribution.J. Pharm. Pharmacol. 35:115–117 (1983).

    Article  CAS  PubMed  Google Scholar 

  21. J. W. Jailer, C. G. Zubrod, M. Rosenfield, and J. A. Shannon. Effect of acidosis and anoxia on the concentration of quinacrine and chloroquine in blood.J. Pharmacol. Exp. Ther. 92:345–351 (1948).

    CAS  PubMed  Google Scholar 

  22. B. B. Brodie, L. C. Mark, E. M. Papper, P. A. Life, E. Bernstein, and E. A. Rovenstine. The fate of thiopental in man and a method for its estimation in biological material.J. Pharmacol. Exp. Ther. 98:85–96 (1950).

    CAS  PubMed  Google Scholar 

  23. W. J. Waddell and T. C. Butler. The distribution and excretion of phenobarbital.J. Clin. Invest. 36:1217–1226 (1957).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. M. L. Chen and W. L. Chiou. Pharmacokinetics of methotrexate and 7-hydroxymethotrexate in rabbits after i.v. administration.J. Pharmacokin. Biopharm. 11:499–513 (1983).

    Article  CAS  Google Scholar 

  25. M. L. Chen, W. P. McQuire, T. E. Lad, and W. L. Chiou. A specific HPLC assay to determine the pharmacokinetics of methotrexate in patients.Int. J. Clin. Pharmacol Ther. Toxicol. 22:1–6 (1984).

    CAS  PubMed  Google Scholar 

  26. A. J. Patterson, W. A. Ritschel, D. Zellner, and S. H. Kim. Methotrexate serum and saliva concentrations in patients.Int. J. Clin. Pharmacol. Ther. Toxicol. 19:381–385 (1981).

    CAS  PubMed  Google Scholar 

  27. L. Kristensen, K. Weismann, and L. Hutters. Renal function and the rate of disappearance of methotrexate from serum.Eur. J. Clin. Pharmacol. 8:439–444 (1975).

    Article  CAS  PubMed  Google Scholar 

  28. D. Bratlid and P. J. Moe. Pharmacokinetics of high-dose methotrexate treatment in children.Eur. J. Clin. Pharmacol. 14:143–147 (1978).

    Article  CAS  PubMed  Google Scholar 

  29. C. F. Stewart, W. R. Crom, W. P. Bowman, P. R. Hutson, and W. E. Evans. Influence of serum concentration on renal clearance of methotrexate in children with acute lymphocytic leukemia.Drug Intell. Clin. Pharm. 16:482 (1982).

    Google Scholar 

  30. D. J. Greenblatt, D. R. Abernethy, and M. Divoll. Is volume of distribution at steady state a meaningful kinetic variable?J. Clin. Pharmacol. 23:391–400 (1983).

    Article  CAS  PubMed  Google Scholar 

  31. W. L. Chiou, C. Y. Lui, and G. Lam. Plasma area method in relative bioavailability evaluation of drugs with changing biological half-lives.J. Pharm. Sci. 70:109–112 (1981).

    Article  CAS  PubMed  Google Scholar 

  32. W. L. Chiou. The physiological significance of the apparent volume of distribution, Vdβ or Vdarea, in pharmacokinetic studies.Res. Commun. Chem. Pathol. Pharmacol. 33:499–508 (1981).

    CAS  PubMed  Google Scholar 

  33. K. C. Huang, B. A. Wenczak, and Y. K. Liu. Renal tubular transport of methotrexate in the rhesus monkey and dog.Cancer Res. 39:4843–4848 (1979).

    CAS  PubMed  Google Scholar 

  34. W. A. Bleyer. The clinical pharmacology of methotrexate.Cancer 41:36–51 (1978).

    Article  CAS  PubMed  Google Scholar 

  35. G. Lam and W. L. Chiou. Determination of the steady-state volume of distribution using arterial and venous plasma data from constant infusion studies with procainamide.J. Pharm. Pharmacol. 34:132–134 (1981).

    Article  Google Scholar 

  36. W. L. Chiou, G. Lam, M. L. Chen, and M. G. Lee. Effect of arterial-venous plasma concentration difference on the determination of mean residence time of drugs in the body.Res. Commun. Chem. Pathol. Pharmacol. 35:17–26 (1982).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, 60612, Chicago, IL

    Chung Y. Lui, Myung G. Lee & Win L. Chiou

Authors
  1. Chung Y. Lui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myung G. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Win L. Chiou
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This research was supported in part by a grant from the National Cancer Institute, CA-29754.

Abstracted from a dissertation submitted in 1984 by Chung Y. Lui to the Graduate College, University of Illinois at Chicago, in partial fulfillment of Doctor of Philosophy Degree requirements.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lui, C.Y., Lee, M.G. & Chiou, W.L. Concentration andpH dependent steady-state volume of distribution of methotrexate estimated by a simple physiologically based method. Journal of Pharmacokinetics and Biopharmaceutics 12, 597–610 (1984). https://doi.org/10.1007/BF01059555

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01059555

Key words

Search

Navigation