Hal 149

Fig. 23 dependence of intenstinal absorbtion on blood flow as reported by winne and remischovsky. All
data are corrected to a concentration of 50 nmol/ml in the solution perfusing jejunal loops of
ratintestine. Brackeled points indicate the 50% confidence intervals. (From Ref.50.)

Of Eq. (7)] may be independent of blood flow. From Fig. 23 it many be seen that the absorbtion of freely
permeable tritiated water is very sensitive to blood flow, but that ribitol, a sugar that penetrates the GI
membrane with great difficulty, is essentially unaffected by changes in the intestinal blood flow in the
range studied. As would be expected from Eq. (7), the absorbtion rate of intermediate subtances, such
as urea, appear to be flow-limited at flow blood flow rates, but then become insensitive to blood flow at
higher rates. Winne and co-workers [48-50] have reported a blood flow dependence for several
relatively small drug molecules. Crouthamel et al. [51] also noted a decrease in the absorbtion rate of
sulfaethidole and haloperidol as a function of decreased mesenteric blood flow rates, using an in situ
canine intestinal preparation. Has and co-workers [52]. Using a guinea pig model, found a strong
correlation between spontaneously varying portal blood flow and the amount of digitoxin and digoxin
absorbed following intraduodenal infusion of the drug. As can be seen in Fig. 24, digitoxin, the most
lipophilic of the three cardiac glycosides, showed the most pronounced effects as a function of blood
flow. However, ouabain, the most hydrophilic of the three, showed no dependence on blood flow.
These results are consistent with the predictions of Eq. (7) for the effects of blood flow on the
absorbtion rate of drugs.

These animal studies should indicate to the pharmacist that blood flow can, under certain
circumstances, be an important patient variable that many effect the absorbtion of drugs. Patients in
heart failure would generally be expected to have a decreased cardiac output and, therefore, a
decreased splanchnic blood flow. This could lead to a decreased rate of absorbtion for drugs when the
blood flow rates in Eq. (7) become rate-limiting. In addition, redistribution of cardiac output during
cardiac failure may lead to splanchnic vasocontriction in patients [53]. other
Hal 150

Fig. 24 total amount of radioactivy absorbed during 1 hr, plotted versus portal versus portal blood flow.
Ordinate: absorpstion as a percentage of the amount infused into the duodenum. Abscissa: mean portal
blood flow in milliliters per minute. Each point represents one guinea pig. (From Ref. 52)

Dicease states and the physical activity can also decrease blood flow to the GIT [2-4]. Thus, the
pharmacist must be aware of the possible importance of blood flow rate, especially alterations in that
rate, on the availability of drugs.

VI. SUMMARY

drug availability following oral dosing may be thought of as the resultant of four basic steps: (a) getting
the drug to its absorbtion site, (b) getting the drug into solution, (c) moving the dissolved drug through
the membranes of the GIT, and (d) moving the drug away from the site of absorption into the general
circulation. Although steps a, c, and d were discussed briefly, these topics are also found in chapters 2
and 5. Step b, the combination of factors influencing the dissolution rate of a drug from its dosage form,
serverd as the major topic of this chapter. Dissolution rate was in terms of the parameters found in the
Nernst-Brunner equation. Although this equation [Eq. (1)] is derived in terms of a specific model for
dissolution, which, in fact, may not accurately describe the physical procces, we believe that the
treatment gives pharmacist a point of reference from which they can predict and interpret availability
data that are rate-limited by the dissolution step. Twp terms in the Nerst-Brunner equation are of major
importance and are susceptible to manipulation by the pharmaceutical manufacturer in preparing the
dosage form, by the patient in the manner in which he or she takes the drug and stores it between drug
dosing, and by the biological system, specifically the GIT of the patient, through interaction with the
dosage form and the drug. These two variable are the surface area ot the drug particles and the
saturation solubility of the particular chemical form of the drug. We believe that pharmacist must be
aware of these variables and how they can change in each of the three situations listed previously
before they can make rational judgments about which of many pharmaceutical alternatives should be
dispensed under a specific set of conditions. Knowledge of these variables and their potential for change
also allows pharmacist to make a rational guess about possibly drug-related factors that may be
responsible fot inefficacious drug threatment. Under these conditions, pharmacist may be able to
recommend an alternative formulation that will prove to be efficacious.
Drug absorption and availability

REFERENCES

1. D. E. Cadwallader, Biopharmaceutic and Drug Interactions, 3rd Ed., Raven Press, New York,
1983.
2. W. H. Bachrach, Physiology of the stomach, Ciba Clin. Symp., 11. 1-28 (1959).
3. W. H. Davenport, Gastric digestion and emptying: Absorption, in Phsysiology of the Digestive
Tract, 3rd Ed., Year Book Medicinal Publishers. Chicago, 1971, pp. 163-171.
4. I. Z. Benet and B. Hoener, Phatological limitations in the application of rate control systems, in
Proceedings of the 2nd International Conference of Drug Absorption Rate Control in Drug
Therapy, (L. Prescott, ed), Edinburgh, 1983, pp. 155-165.
5. G. D. Kozloski, J. M. De Vito, J. C. Kisicki, and J. B. Johnson, The effect of food on the absorption
of methotrexate sodium tablets in healty volunteers, Arthritis Rheum, 35. 761-764 (1992).
6. P. G. Welling, H. Huang, P. F. Hewitt, and L. L. Lyons, Bioavalability of erythromycin stearate:
Influence of food and fluid volume, J. pharm. Sci., 67. 764-766 (1978).
7. T. R. Bates, J. A. Sequeria, and A. V. Tembo, Effect of food on nitrofurantoin absortion, Clin.
Pharmacol. Ther., 16. 63-68 (1974).
8. J. W. Fara, Psysiological limitations: Gastric empetying and transit of dosage forms, in
Proceedings of the 2nd International Conference on Drug Absorption, Rate Control in Drug
Therapy (L. Prescott, ed), Edinburgh, 1983, pp. 144-150.
9. C. P. Dooley, C. Di Lorenzo, and J. E. Velenzuela, Variability of migrating motor complex in
humans, Dig. Dis. Sci., 37. 723-728 (1992).
10. V. Manninen, J. Melin, A. Apajalahti, and M. Karesoja, Altered absorption of digoxin in patients
given propantheline and metoclopramide, Lancet., 1. 398-400 (1973).
11. C. G. Regardh, P. Lundborg, and B. A. person, The effect of antacid, metoclopramide and
propantheline on the bioavailability of metoprolol and atenolol. Biopharm. Drug Dispons., 2. 79-
87 (1981).
12. J. A. Antonioli, J. L. Schelling, E. Steininger, and G. A. Borel, Effect of gastrecnomy and of an
anticholinergic drug on the gastrointestinal absorption of a sulfonamide in man, Int. J. Clin.
Pharmacol., 5. 212-215 (1971).
13. W. H. Barr and S. Riegelman, Intestinal drug absorption and metabolism. I. Comparison of
methods and models to study physiological factors in vitro and in vivo intestinal absorption, J.
pharm. Sci., 59. 154-163 (1970).
14. W. H. Barr and S. Riegelman, intestinal drug absorption and metabolism. II. Kinetic aspect of
intestinal glucuronide conjugation, J. pharm. Sci., 59. 164-168 (1970).
15. J. C. Kolars, P. Schmiedlin-Ren, J. D. Schuetz, C. Fang, and P. B. Watkins, Indentification of
rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes, J. Clin. Invest., 90.
1871-1878 (1992).
16. R. R. Scheline, Metabolism of foreign compounds by gastrointestinal microorganisms,
Pharmacol. Rev., 25. 451-523 (1973).
17. L. Z. Benet, Bioparmaceutics as a basis for the design of drug products, in Drug Design, Vol.4 (E.
J. Ariens, Ed.), Academic Press, New York, 1973, pp. 1-35.
18. W. Nernst and E. Brunner, Z. Phys. Chem., 47. 52-106 (1904).
 19. P. Finholt, Influence of formulation on dissoulution rate, in Dissolution Technology (L. J. Leeson
and J. T. Carstensen, eds.), Academy of Pharmeceutical Sciences, American Pharmaceutical
Association, Washington, DC, 1974, pp. 106-146.
20. L. F. Prescott, R. F. Steel, and W. R. Ferrier, The effects of particle size on the absorption of
phenacetin in man, Pharmacol. Ther., 11. 496-504 (1970).
21. A. J. Glazko, A. W. Kinkel, W. C. Alegnani, and E. L. Holmes, an evaluation of the absorption
characteristics of different chloramphenicol preparations in normal human subject, Clin.
Pharmacol. Ther., 9. 472-483 (1968).
22. K. Arnold, N. Gerber, and G. Levy, Absorption and dissolution studies on sodium
diphenylhydantoin capsules, Can. J. pharm. Sci., 5. 89-92 (1970).
23. G. Levy and R. H. Gumtow, Effect of certain tablet formulation factors on dissolution rate of the
active ingredient. III. Tablet lubricants, J. pharm. Sci., 52. 1139-1141 (1963).

Hal 152

24. G. levy J. M. Antkowiyak. J. A. Procknal, and D. C. White , Effect of certain tablet formularium
factors on dissolution rate of the active ingredients. II Granule size, starch concertation, and
compression pressure. J. Pharm. Sci., 52. 1047-1051 (1963).
25. J. C. samyn and W. Y. Jung, in vitro dissolution from several experimental capsule formulations, J.
Pharm, Sci., 59. 169-175 (1970).
26. S. H. wan. P. J. pentikainen, and D. L. Azarnoff. Biovailabiliity of aminosalicylic acid and its various
salts in humans. III. Absorbtion from tablets, J. Pharm. Sci., 63. 708-711 (1974)
27. E. Nelson. Influence dissolution rate and surface on tetracycline absorption. J. Am. Pharm. Assocl.
Sci. Ed., 48. 96-103 (1959)
28. E. Nelson, E. L. Knoechel, W. E. Hamlin. And J. G. Wagner, Influence of the absorbtion rate of
tolbutamide on the rate of decline of blood sugar levels in normal humans, J. Pharm. Sci., 51. 509-
514 (1962)
29. C. C. Lee. R. O. Froman. R. C. Anderson, and K. C. Chen, Gastric and intestinal absorption of
potassium penicillin V ad the free acid, antibiot, chemother., 8. 354-360 (1958)
30. G. Levy and B. A. Sannai, Comparison of the gastrointestinal absorption of aluminum acetylsalicylic
and acetylsalicylic acid in man, J. Pharm. Sci., 51. 58-62 (1962)
31. R. A. OReilly, E. Nelson, and G. Levy, Physicochemical and physiologic factors affecting the
absorption of warfarin in man, J. Pharm. Sci., 55. 435-437 (1966)
32. W. I. Higuchi and W. E. Hamlin, Release of drug from a self-coating surface: Benzpetamine
pamoate pellet, J. Pharm. Sci., 52. 575-579 (1963)
33. E. Nelson, comparative dissolution rates of weak acids and their sodium salts, J. Am. Pharm. Assoc.
Sci. Ed., 47. 297-299 (1958)
34. T. R. Bates, J. M. Young, C. M. Wu, and H. A. Rosenberg, pH-dependent dissolution rate of
nitrofurantoin from commercial suspensions, tablets and capsules, J. Pharm. Sci., 54. 1719-1722
(1966)
35. G. Levy. J. R. Leonards, and J. A. Procknal, Development of in vitro dissolution tests which correlate
quantitatively with dissolution rate-limited drug absorption in man. J. Pharm. Sci., 54. 1719-1722
(1966)
36. K.A. Javaid and D. E. Cadwallader, Dissolution of aspirin from tablets containing various buffering
agents, J. Pharm. Sci., 1370-1373 (1972)
37. J. W. Poole, G. Owen, J. Silverio, J. N. freyhot, and S. B. Roseman, Physicochemical factors
influencing the absorption of the anhydrous and irihydrate form of ampicillin, Curr. Ther. Res. 10.
292-303 (1968)
38. J. Hableblian and W. McCone, Pharmaceutical applications of polymorphism, J. Pharm. Sci., 58.
911-929 (1969)
39. A. J. Aguiar, J. Krc. A. W. Kinkel, and J. C. Samyn, Effect of polymorphism on the absorption at
chloramphenicol palminate, J. Pharm. Sci., 56. 847-853 (1967)
40. D. L. Sorby, Effect of adsorbents on drug absorption. I. Modification of promazine absorption by
activated attapulgite and activated charcoal, J. Pharm. Sci., 54. 677-683 (1965)
41. K. C. Kwan and D. J. Allen, Determination of the degree of crystallinity in solid-solid equilibria. J.
Pharm. Sci., 58. 1190-1193 (1969)
42. E. N. Hiestand. W. I. Higuchi, and N. F. H. Ho, Theories of dispersion techniques, in the theory and
Practice of Industrial Pharmacy, 2nd Ed. (L. Laehman, H.A. Lieberman, and J. L. Kanig, eds). Lea &
Febriger, Philadelphia, 1976, p. 159.
43. A. H. Goldberg, M. Gibaldi, and J. L. Kanig, Increasing dissolution rates and gastrointestinal abfulvin
succinic acid solid solution, J. Pharm. Sci., 55. 487-492 (1966)
44. A. Goldberg, Methods of increasing dissolution rates, in Dissolution Technology (I. J. Lesson and J.
T. Cartensen, eds). Academy of pharmaceutical Science, American Pharmaceutical Association,
Washington, DC. 1974, pp. 147-162
45. L. Z. Benet, Theories of dissolution: Multi-particulate systems, in Dissolution Technology (I. J.
Leeson and J.T. Cartensen, eds). Academy of Pharmaceutical Sciences, American Pharmaceutical
Association, Washington, DC, 1974, pp. 29-57
Hal.153

Drug absorption and availability

46. L. Z. Benet, A. Greither, and W. Meister. Gastrointestinal absorption of drug in patients with
cardiac failure, in The Effect of Disease States an Drug Pharmacokinetics (L. Z. Benet, ed),
Academy of Pharmaceutical Association, Washington, D.C., 1976, pp. 33-50.
47. L. Ther and D. Winne, Drug absorption, annu. Rev. Pharmacol., 11. 57-70 (1971)
48. D. Winne and H. Ochsenfahrt, Die formale Kinetic der Resoption unter Bercksichtigung der
Darmdurchblutung, J. Theor. Biol., 14, 293-315 (1967)
49. D. Winne, The influence of villous countercurrent exchange on intestinal absorption, J. Theor.
Biol., 53. 145-176 (1976)
50. D. Winne and J. Remischovsky, Intestinal blood flow and absorption of nondissociable subtances,
J. Pharm. Pharmacol. 22. 640-641 (1970)
51. W. G. Crouthamel, L. Diamond, L. W. Ditterl, and J. T. Doluisio, Drug absorption. VII. Influence of
mesenteric blood flow on intestinal drug absorption in dogs, J. Pharm, Sci., 64. 661-671 (1975)
52. A. Haas, H. Lullman, and T. Peters, Absorbtion rates of some cardiac glycosides and portal blood
flow, Eur. J. pharmacol., 19. 366-370 (1972)
53. J. Ferrer, S. E. Bradley, H. O. Wheeler, Y. Enson, R. presig, and R. M. Harvey, The effect of dixogin
on the spanchnic ciuculation in ventricular failure, Circulation, 32. 524-537 (1965)