Pharmaceutical Research

, Volume 11, Issue 1, pp 136–143

pH-Related Changes in the Absorption of Dipyridamole in the Elderly

  • Tanya L. Russell
  • Rosemary R. Berardi
  • Jeffrey L. Barnett
  • Tami L. O’Sullivan
  • John G. Wagner
  • Jennifer B. Dressman
Article

Abstract

The bioavailability of dipyridamole, a poorly soluble weak base, was evaluated in 11 healthy, older subjects (≥65 years), 6 with a low fasting gastric pH (control) and 5 with a fasting gastric pH > 5 (achlorhydric), in a randomized, crossover design. Subjects received 50 mg dipyridamole as a single oral dose both with and without pretreatment with 40 mg famotidine (control subjects) or 1360 mg glutamic acid HC1 (achlorhydric subjects). Gastric pH was monitored by Heidelberg radiotelemetric capsule. Gastric emptying of 99mTc-radiolabeled orange juice was measured. Gastric pH appeared to be a primary determinant in dipyridamole absorption in the elderly. Elevated gastric pH resulted in compromised dipyridamole absorption compared to low-gastric pH conditions in all cases. The administration of glutamic acid hydrochloride to achlorhydric subjects prior to the dose of dipyridamole corrected for the decreased Cmax and AUC(0–36) exhibited in achlorhydric subjects without pretreatment. Tmax and ka were slower in achlorhydrics, although pretreatment with glutamic acid HC1 tended to normalize these parameters. Based on these results, it would be beneficial for achlorhydrics to take glutamic acid hydrochloride prior to taking dipyridamole and other medications which need a low gastric pH for complete absorption. The administration of 40 mg famotidine was successful in elevating the gastric pH to >5 in all subjects and maintained it at >5 for at least 3 hr in all subjects tested. The lack of differences in Cmax and AUC(0–36) with significant differences in Tmax and ka indicated that control subjects after treatment with famotidine may serve as an adequate model for achlorhydrics with respect to the extent of absorption, but not with respect to the rate of absorption. Gastric emptying of a nutrient liquid was significantly slower in achlorhydric subjects than in control subjects. Finally, fasting serum gastrin appeared to be a relatively reliable and easy method for screening for achlorhydria in the elderly.

elderly drug absorption gastric pH gastric emptying dipyridamole glutamic acid hydrochloride famotidine Heidelberg radiotelemetric capsule 

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REFERENCES

  1. 1.
    T. L. Russell, R. R. Berardi, J. L. Barnett, L. C. Dermentzoglou, K. M. Jarvenpaa, S. P. Schmaltz, and J. B. Dressman. Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women. Pharm. Res. 10 (2):187–196 (1993).Google Scholar
  2. 2.
    W. T. Davies and J. R. Kirkpatrick. Gastric emptying in atrophic gastritis and carcinoma of the stomach. Scand. J. Gastroenterol. 6:297 (1971).Google Scholar
  3. 3.
    J. S. Fordtran and J. H. Walsh. Gastric acid secretion rate and buffer content of the stomach after eating. J. Clin. Invest. 52:645–657 (1973).Google Scholar
  4. 4.
    USP-DI Drug Information for the Health Care Professional, United States Pharmacopeial Convention, Inc., Rockville, MD, 1991, pp. 1171–1173.Google Scholar
  5. 5.
    Facts and Comparisons, J. B. Lippincott, St. Louis, MO, 1990, pp. 85a–85b.Google Scholar
  6. 6.
    W. O. Foye. Principles of Medicinal Chemistry, Lea and Febiger, Philadelphia, 1981.Google Scholar
  7. 7.
    L. C. Dermentzoglou. Changes in Upper Gastrointestinal pH with Aging: Implications for Drug Absorption, Doctoral thesis, University of Michigan, Ann Arbor, 1989.Google Scholar
  8. 8.
    J. B. Dressman, R. R. Berardi, L. C. Dermentzoglou, T. L. Russell, S. P. Schmaltz, J. L. Barnett, and K. M. Jarvenpaa. Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm. Res. 7 (7):756–761 (1990).Google Scholar
  9. 9.
    M. J. Knapp, R. R. Berardi, J. B. Dressman, J. M. Rider, and P. L. Carver. Modification of gastric pH with oral glutamic acid hydrochloride. Clin. Pharm. 10:866–870 (1991).Google Scholar
  10. 10.
    K. M. Wolfram and T. D. Bjornsson. High-performance liquid chromatographic analysis of dipyridamole in plasma and whole blood. J. Chromatogr. 183:57–64 (1980).Google Scholar
  11. 11.
    J. G. Wagner and E. Nelson. Percent absorbed time plots derived from blood level and/or urinary excretion data. J. Pharm. Sci. 52:610–611 (1963).Google Scholar
  12. 12.
    J. G. Wagner, D. A. Ganes, K. K. Midha, I. Gonzalez-Younes, J. C. Sackellares, L. D. Olsen, M. B. Affrime, and J. E. Patrick. Stepwise determination of multicompartment disposition and absorption parameters from extravascular concentration-time data. Application to mesoridazine, flurbiprofen, flunarizine, labetalol, digoxin and diazepam. J. Pharmacokin. Biopharm. 19 (4):413–455 (1991).Google Scholar
  13. 13.
    J. C. K. Loo and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs. J. Pharm. Sci. 57 (6):918–927 (1968).Google Scholar
  14. 14.
    J. G. Wagner. Pharmacokinetic absorption plots from oral data alone or oral/intravenous data and an exact Loo-Riegelman equation. J. Pharm. Sci. 72 (7):838–842 (1983).Google Scholar
  15. 15.
    J. H. Proost. Wagner's exact Loo-Riegelman equation: The need for a criterion to choose between the linear and logarithmic trapezoidal rule. J. Pharm. Sci. 74 (7):793–794 (1985).Google Scholar
  16. 16.
    J. L. Fleiss. The crossover study. In The Design and Analysis of Clinical Experiments, John Wiley and Sons, New York, 1986, pp. 263–290.Google Scholar
  17. 17.
    N. Kohri, N. Miyata, M. Takahashi, H. Endo, K. Iseki, K. Miyazaki, S. Takechi, and A. Nomura. Evaluation of pH-independent sustained-release granules of dipyridamole by using gastric-acidity-controlled rabbits and human subjects. Int. J. Pharm. 81:49–58 (1992).Google Scholar
  18. 18.
    P. Lelawongs, J. A. Barone, J. L. Colaizzi, A. T. M. Hsuan, W. Mechlinski, R. Legendre, and J. Guarnieri. Effect of food and gastric acidity on absorption of orally administered ketoconazole. Clin. Pharm. 7:228–235 (1988).Google Scholar
  19. 19.
    R. R. Recker. Calcium absorption and achlorhydria. N. Engl. J. Med. 313 (2):70–73 (1985).Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Tanya L. Russell
    • 1
  • Rosemary R. Berardi
    • 1
  • Jeffrey L. Barnett
    • 3
  • Tami L. O’Sullivan
    • 1
  • John G. Wagner
    • 1
    • 5
  • Jennifer B. Dressman
    • 1
  1. 1.College of PharmacyThe University of MichiganAnn Arbor
  2. 2.Marion Merrell Dow Inc.Kansas City
  3. 3.School of MedicineThe University of Michigan HospitalAnn Arbor
  4. 4.Detroit Receiving HospitalDepartment of PharmacyDetroit
  5. 5.The University of MichiganUSA

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