Abstract
The in vitro Ussing technique was employed to examine transport rates for acetaminophen and arginine across rabbit intestinal tissues. Mannitol and transepithelial conductance were used to monitor the integrity of rabbit intestinal tissues and the basal and stimulated short-circuit current were measured to assess functional viability. Transepithelial transport of acetaminophen, arginine, and mannitol was determined in rabbit jejunum, ileum, and distal colon. Transepithelial transport of arginine in the ileum and jejunum was composed of both passive (nonsaturable) (P m = 0.06) and saturable components (K T = 0.6-0.7 mM; J max = 0.3-0.4 µmol/hr · cm2). The saturable component of arginine fluxes was abolished by pretreatment of the tissue with serosal ouabain (0.1 mM). In the distal colon, both unidirectional arginine fluxes were nonsaturable. In the segments examined, both unidirectional fluxes of acetaminophen were nonsaturable over the concentration range from 0.1 to 30 mM. These results provide values for maximal permeabilities attained by molecules traversing both the cellular and the paracellular pathways and, by comparison to their in vivo bioavailabilities, provide selection criteria for evaluating drug candidates for oral activity.
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REFERENCES
H. H. Ussing and K. Zerahn. Active transport of sodium as the source of the electric current in the short-circuited isolated frog skin. Acta Physiol. Scand. 19:43–56 (1951).
D. Dawson. Na and Cl transport across the isolated turtle colon: Parallel pathways for transmural ion movement. J. Membr. Biol. 37:213–233 (1977).
P. L. Smith and R. D. McCabe. A23187-induced changes in colonic K and Cl transport are mediated by separate mechanisms. Am. J. Physiol. 247:G695–G702 (1984).
P. Smith, C. Mirabelli, J. Fondacaro, F. Ryan, and J. Dent. Intestinal 5-fluorouracil absorption: Use of Ussing chambers to assess transport and metabolism. Pharm. Res. 5:598–603 (1988).
A. Burr, A. Yamamoto, and V. H. L. Lee. Penetration of 5-fluorouracil and prodrugs across the intestine of the albino rabbit: Evidence for shift in absorption site from the upper to the lower region of the gastrointestinal tract by prodrugs. J. Control. Rel. 14:43–51 (1990).
B. Matuszewska, G. G. Liversidge, F. Ryan, J. Dent, and P. L. Smith. In vitro study of intestinal absorption and metabolism of 8-L-arginine vasopressin and its analogues. Int. J. Pharm. 46:111–120 (1988).
S. M. Rogers and D. J. Back. The use of Ussing chambers for the study of intestinal metabolism in vitro. In A. S. Koster, E. Richter, F. Lauterbach, and F. Hartmann (eds.), Progr. Pharmacol. Clin. Pharmacol., Gustav Fischer Verlag, Stuttgart, 1989, pp 43–53.
F. M. Ryan, J. F. Newton, R. D. Eckardt, and P. L. Smith. Transport and metabolism of SK&F 104353 in rabbit intestine in vitro: Preferential absorption by ileum. Pharm. Res. 5:S-104 (1988).
S. G. Schultz. Sodium-coupled solute transport by small intestine: A status report. Am. J. Physiol. 233:E249–E254 (1977).
C. L. Corbett, P. E. T. Isaacs, A. K. Riley, and L. A. Turnberg. Human intestinal transport in vitro. Gut 18:136–140 (1977).
R. A. Frizzell and K. Heintze. Electrogenic chloride secretion by mammalian colon. In H. J. Binder (ed.), Mechanisms of Intestinal Secretion, Alan R. Liss, New York, 1979, pp. 101–116.
R. C. Rose and S. G. Schultz. Studies on the electrical potential profile across rabbit ileum. J. Gen. Physiol. 57:639–663 (1971).
S. G. Schultz and R. Zalusky. Ion transport in isolated rabbit ileum. I. Short-circuit current and Na+ fluxes. J. Gen. Physiol. 47:567–584 (1964).
R. D. McCabe, P. L. Smith, and L. P. Sullivan. Ion transport by rabbit descending colon: Mechanisms of transepithelial potassium transport. Am. J. Physiol. 246:G594–G602 (1984).
M. J. Welsh and J. H. Widdcombe. Pathways of ion movement in the canine tracheal epithelium. Am. J. Physiol. 239:F215–F221 (1980).
G. J. Marks, F. M. Ryan, I. J. Hidalgo, and P. L. Smith. Mannitol as a marker for intestinal integrity in in vitro absorption studies. Gastroenterology 100:A697 (1991).
P. L. Smith and M. Field. In vitro antisecretory effects of trifluoperazine and other neuroleptics in rabbit and human small intestine. Gastroenterology 78:1545–1553 (1980).
R. A. Frizzell, M. J. Koch, and S. G. Schultz. Ion transport by rabbit colon. I. Active and passive components. J. Membr. Biol. 27:297–316 (1976).
S. K. Sullivan and P. L. Smith. Bicarbonate secretion by rabbit proximal colon. Am. J. Physiol. 251:G436–G445 (1986).
U. Hopfer. Membrane transport mechanisms for hexoses and amino acids in the small intestine. In L. R. Johnson (ed.), Physiology of the Gastrointestinal Tract, Raven Press, New York, 1987, pp. 1499–1526.
M. D. Rawlins, D. B. Henderson, and A. R. Hijab. Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration. Eur. J. Clin. Pharmacol. 11:283–286 (1977).
M. F. Laker, H. J. Bull, and I. S. Menzies. Evaluation of mannitol for use as a probe marker of gastrointestinal permeability in man. Eur. J. Clin. Invest. 12:485–491 (1982).
P. L. Smith, D. A. Wall, C. H. Gochoco, and G. Wilson. Routes of delivery: Case study. Oral absorption of peptides and proteins. Adv. Drug Del. Rev. 8:253–290 (1992).
I. S. King, F. V. Sepulveda, and M. W. Smith. Cellular distribution of neutral and basic amino acid transport systems in rabbit ileal mucosa. J. Physiol. 319:355–368 (1981).
J. Y. F. Paterson, F. V. Sepulveda, and M. W. Smith. Distinguishing transport systems having overlapping specificities for neutral and basic amino acids in the rabbit ileum. J. Physiol. 319:345–354 (1981).
B. G. Munck. Transport of neutral and cationic amino acids across the brush-border membrane of the rabbit ileum. J. Membr. Biol. 83:1–13 (1985).
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Swaan, P.W., Marks, G.J., Ryan, F.M. et al. Determination of Transport Rates for Arginine and Acetaminophen in Rabbit Intestinal Tissues in Vitro . Pharm Res 11, 283–287 (1994). https://doi.org/10.1023/A:1018967727156
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DOI: https://doi.org/10.1023/A:1018967727156