Does Fluid Flow Across the Intestinal Mucosa Affect Quantitative Oral Drug Absorption? Is It Time for a Reevaluation?
- Hans Lennernäs
- … show all 1 hide
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Purpose. Hydrophilic and charged solutes have a lower membrane permeability which is due to a lower partition into the lipid membrane (low solubility in the membrane phase) and/or a slower transcellular diffusion coefficient. They are therefore anticipated to be absorbed through the paracellular route, which is a consequence of diffusion and a convective volume flow through the water-filled intercellular space.
Methods. Two approaches have been used to investigate the mechanisms underlying the paracellular drug transport across the intestinal mucosa: (a) including water transport by exposing the apical side of the epithelium with a hypotonic solution, and (b) stimulated paracellular transport by widening of tight junction and increased water absorption as a consequence of the sodium-coupled transport of nutrients.
Results. Among the first studies that recognized this fluid flux dependent transmucosal transport of drugs, was one published by Oschenfahrt & Winne in 1973 and the one by Kitazawa et al. in 1975. During the last two decades the importance of this paracellular route for drug delivery have been explored in vitro and in situ.
Conclusions. The limits concerning molecular weight, shape, ionization and the effect of physiological stimulants, such as luminal concentrations of nutrients, osmolality and motility, are currently under investigation. However, recently published in vivo human data by ourselves and others indicate that the promising results obtained in vitro and in situ for various hydrophilic compounds might not be valid in quantitative aspects in humans, especially not for drugs with a molecular weight over 200.
- N.H. Nellans. (B) Mechanisms of peptide and protein absorption. (1) Paracellular intestinal transport: modulation of transport. Adv. Drug Delivery; 7:339–64 (1991).
- L. Narawane and V. H. L. Lee. Absorption barriers,. In A. G. de Boer (ed), Drug Absorption Enhancement, Concepts, Possibilities, Limitations and Trends, Harwood Academic Publishers, Chur, Switzerland, 1994, pp. 1–66.
- A.B.J. Noach, M. A. Hurni, A. G. de Boer and D.D. Brimer. Absorption barriers, In A. G. de Boet (ed), Drug Absorption Enhancement, Concepts, Possibilities, Limitations and Trends, Harwood Academic Publishers, Chur, Switzerland, 1994, pp. 291–324.
- B. Andersson and H.H. Ussing. Solvent drag on nonelectrolytes during osmotic flow through isolated toad skin and its response to antidiuretic hormone. Acta Physiol. Scand. 39, 228–239 (1957).
- D. C. Taylor. Sites and mechanisms of intestinal drug absorption. Pharm. Int. 6, 179–183 (1986).
- D. C. Taylor, R. Pownall and W. Burke. The absorption of β-adrenoceptor antagonists in rat in situ small intestine; the effect of lipophilicity J. Pharm. Pharmacol. 37, 280–283 (1985).
- P. Artursson and C. Magnusson. Epithelial transport of drugs in cell culture. II: Effect of extracellular calcium concentration on the paracellular transport of drugs of different lipophilicities across monolayers of intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 79, 595–600 (1990).
- J.R. Pappenheimer and K.Z. Reiss. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membr. Biol. 100, 123–136 (1987).
- J.L. Madara and J.R. Pappenheimer. Structural Basis for physiological regulation of paracellular pathways in intestinal epithelia. J. Membrane Biol. 100, 149–164 (1987).
- R.A. Frizzell and S.G. Schultz. Ionic conductance of extracellular shunt pathway in rabbit ileum. J. Gen. Physiol. 59;318–346 (1972).
- H-H. Lu, J. Thomas J and D. Fleisher. Influence of D-glucoseinduced water absorption on rat jejunal uptake of two passively absorbed drugs. J. Pharm. Sci. 81:21–5 (1992).
- H-H. Lu, J. Thomas, J. Tukker and D. Fleisher. Intestinal water and solute absorption studies: Comparison of in situ perfusion with chronic isolated loops in rats. Pharm. Res. 9:894–900 (1992).
- H. Ochsenfahrt and D. Winne. The contribution of solvent drag to the intestinal absorption of tritiated water and urea from the jejunum of the rat. N-Schmied. Arch. Pharmacol. 279:133–152 (1973).
- H. Ochsenfahrt and D. Winne. The contribution of solvent drag to the intestinal absorption of the basic drugs amidopyrine and antipyrine from the jejunum of the rat. N-Schmied. Arch. Pharmacol. 281:175–196 (1974).
- H. Ochsenfahrt and D. Winne. The contribution of solvent drag to the intestinal absorption of the acidic drugs benzoic acid and salicylic acid from the jejunum of the rat. N-Schmied. Arch. Pharmacol. 281:197–217 (1974).
- S. Kitazawa, H. Ito and H. Sezaki. Transmucosal fluid movement and its effect on drug absorption. Chem. Pharm. Bull. 23:1856–1865 (1975).
- S. Kitazawa, H. Ito, I. Johno, T. Takahashi and H. Takenaka. Generality in effects of transmucosal fluid movement and glucose on drug absorption from the rat small intestine. Chem. Pharm. Bull. 26:915–924 (1978).
- A. Karino, M. Hayashi, S. Awazu and M. Hanano. Solvent drag effect in drug intestinal absorption. II. Studies on drug absorption clearance and water influx. J. Pharm. Dyn. 5:670–677 (1982).
- T. Hirasawa, T. Muraoka, A. Karino, M. Hayashi and S. Awazu. Solvent drag in jejunal absorption of salicylic acid and antipyrine obtained by in situ single-pass perfusion method in rat. J. Pharm. Dyn. 7:246–253 (1984).
- P. Krugliak, D. Hollander, T.Y. Ma, D. Tran, V.D. Dadufalza, K.D. Katz and K. Le. Mechanisms of polyethylene glycol 400 permeability of perfused rat intestine. Gastroenterol. 97:1164–1170 (1989).
- D. Fleisher, N. Sheth, H. Griffin, M. Mcfadden and G. Aspachar. Nutrient influences on rat intestinal phenytoin uptake. Pharm. Res. 6, 332–337 (1989).
- N. See and P. Bass. Nutrient-induced changes in the permeability of the rat jejunal mucosa. J. Pharm. Sci. 82:721–4 (1993).
- I. Johno, K. Kawakatsu, H. Kuwata and S. Kitazawa. Segmental difference in transmucosal fluid movement and its effect on gastrointestinal drug absorption in rabbits. Int. J. Pharm. 25;255–263 (1985).
- O. Kedem and A. Katchalsky. Thermodynamics of flow processes in biological systems. Biophys. J., Suppl. 53–78 (1958).
- H. Lennernäs, D. Nilsson, S-M. Aquilonius, Ö. Ahrenstedt, L. Knutsson and L. Paalzow. The effect of L-leucine on the absorption of levodopa, studied by regional jejunual perfusion in man. Br. J. Clin. Pharmacol. 35, 243–250 (1993).
- H. Lennernäs, Ö. Ahrenstedt and A-L. Ungell. Intestinal drug absorption during induced net water absorption in man: A mechanistic study using antipyrine, atenolol and enalaprilat. Br. J. Clin. Pharmacol. 37, 589–596, (1994).
- D. Nilsson, U. Fagerholm and H. Lennernäs. The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum. Pharm. Res., 11, 1541–1545 (1994).
- U. Fagerholm, L. Borgström, Ö. Ahrenstedt and H. Lennernäs. The lack of effect of induced net fluid absorption on the in vivo permeability of terbutaline in the human jejunum. J. Drug Targeting, in press, (1995).
- K.D. Fine, C.A. Santa Ana, J. L. Porter and J.S. Fordtran. Effect of D-glucose on intestinal permeability and its passive absorption in human small intestine in vivo. Gastroenterol., 105;1117–1125 (1993).
- K.H. Soergel. Showdown at the tight junction. Gastroenterol., 105:1247–1250 (1993).
- B. G. Munck and S. N. Rasmussen. Paracellular permeability of extracellular space markers across rat jejunum in vitro. Indication of a transepithelial fluid circuit. J. Physiol., 271;473–488 (1977).
- W.D. Stein. Transport and Diffusion across Cell Membranes. Academic Press, Inc. Harcourt Brace Jovanovich, Publishers, New York, 1986. Press, Cambridge, 1984., pp. 8–112.
- S. Tripathi and E. L. Boulpaep. Mechanisms of water transport by epithelial cells. Quarterely J. Exp. Physiol. 74; 385–417 (1989).
- C. H. van Os., P. M. T. Deen and J. A. Dempster. Aquaporins: water selective channels in biological membranes. Molecular structure and tissue distribution. Biochimica et Biophysica Acta 1197;291–309 (1994).
- G. I. Sandle, M.J., Keir and C. O. Record. Inter-relationships between the absorptions of hydrocortisone, sodium, water and actively transported organic solutes in the human jejunum. Eur. J. Clin. Pharmacol. 23:177–182 (1982).
- K.D. Fine, C. A. Santa Ana, J.L. Porter and J.S. Fordtran. Mechanism by which glucose stimulates the passive absorption of small solutes by the human jejunum in vivo. Gastroenterol., 107;389–395 (1994).
- J.L. Madara and J. S. Trier. The functional morphology of the mucosa of the small intestine. Physiology of the Gastrointestinal Tract, ed Johnson L.R., Raven Press, New York, 1994, pp 1577–1622.
- H. Lennernäs, Ö. Ahrenstedt, R. Hällgren, L. Knutsson, M. Ryde, L. Paalzow Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm. Res. 9;1243–1251 (1992).
- K. Atisook and J. L. Madara. An oligopeptide permeates intestinal tight junctions at glucose-elicited dilatations. Gastroenterol. 100; 719–724 (1991).
- P. Claude. Morphological factors influencing transepithelial permeability: a model for the resistance of the Zonula Occludens. J. Membrane Biol. 39;219–232 (1978).
- J. A. Bastidas, M. J. Zinner, J. A. Bastidas, M. S. Orlandle and J. L. Yeo. Influence of meal composition on canine jejunal water and electrolyter absorption. Gastroenterology. 102;486–492 (1992).
- M. D. Donovan, G. L. Flynn and G.L. Amidon. Absorption of polyethylene glycols 600 through 2000: the molecular weight dependence of gastrointestinal and nasal absorption. Pharm. Res. 7, 863–868 (1990).
- V. S. Chadwick, S. F. Phillips and A. F. Hofmann. Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). II. Application to normal and abnormal permeability states in man and animals. Gastroenterology. 73, 247–251 (1977).
- Y.C. Martin. A practitioner's perspective of the role of quantitative structure-activity analysis in medicinal chemistry. J. Med. Chem. 24, 229–237 (1981).
- A. C. Chakrabarti. Permeability of membranes to amino acids and modified amino acids: mechanisms involved in translocation. Amino Acids, 6; 213–229 (1994).
- A. Walter and J. Gutknecht. Permeability of small nonelectrolytes through lipid bilayer membranes. J. Membrane Biol. 90, 207–217 (1986).
- E. Overton. Ueber die allgemeinen osmotischen eigenschaften der zelle, ihre vermutlichen ursachen und ihre bedeutung fur die physiologie. Vierteljahrsschr. Naturforsch. Ges. Zuerich., 44;88–135 (1899).
- R. Collander. The permeability of plant protoplasts to small molecules. Physiol. Plant. 2;300–311 (1949).
- U. Fagerholm and H. Lennernäs. Experimental Estimation of the Effective Unstirred Water Layer Thickness in the Human Jejunum, and its Importance in Oral Drug Absorption. Eur. J. Pharm. Sci. in press (1995).
- M. Cereijido, A. Ponce and L. González-Mariscal. Tight junctions and apical/basolateral polarity. J. Membrane Biol. 110;1–9 (1989).
- M. Jodal and O. Lundgren. Countercurrent mechanisms in the mammalian gastrointestinal tract. Gastroenterol. 91;225–241 (1986).
- G. J. Anthone, B. H. Wang, M. J. Zinner, M. S. Orandle and C. J. Yeo. Meal-induced jejunal absorption requires intact neural pathways. Am. J. Surgery, 163;150–156 (1992).
- C.J. Yeo, A. Bastidas, R.E. Schmieg and M. J. Zinner. Mealstimulated absorption of water and electrolytes in canine jejunum. Am. J. Physiol. 259;G402–G409 (1990).
- J. B. Hunt, R. J. Elliott and M. J. G. Farthing. Comparison of rat and human intestinal perfusion models for assessing efficacy of oral rehydration solutions. Aliment. Pharmacol. Therap., 5;49–59 (1991).
- D. C. Sadoiwski and J. B. Meddings. Luminal nutrients alter tight-junction permeability in the rat jejunum: an in vivo perfusion model. Can. J. Physiol. Pharmacol., 71; 835–839 (1993).
- T. Y. Ma, D. Hollander, R. A. Erickson, H. Truong, H. Nguyen and P. Krugliak. Mechanism of colonic permeation of inulin: Is rat colon more permeable than small intestine? Gastroenterol., 108;12–20 (1995).
- A.B.J. Noach, M. Sakai, M. C. M. Blom-Roosemalen, H. R. de Jonge, A. G. de Boer and D.D. Breimer. Effect of anistotonic conditions on the transport of hydrophilic model compounds across monolayers of human colonic cell lines. J. Pharmacol. Exp. Ther., 270; 1373–1380 (1994).
- J. Karlsson, Drug absorption in cell culture models of the intestinal epithelium, thesis, the university of Uppsala, Sweden, (1995).
- M. Peeters, M. Hiele, Y. Ghoos, V. Huysmans, K. Geboes, G. Vantrappen and P. Rutgeerts. Test conditions greatly influence permeation of water soluble molecules through the intestinal mucosa: need for standardisation. Gut., 35, 1404–1408 (1994).
- C. V. Gisolfi, R. W. Summers, H. P: Schedl and T. L. Bleiler. Intestinal water absorption from select carbohydrate solutions in humans. J. Appl. Physiol. 73;2142–2150 (1992).
- T. Gramatté, E. El Desoky and U. Klotz. Site-dependent small intestinal absorption of ranitidine. Eur. J. Clin. Pharmacol. 46; 253–259 (1994).
- R. P. Ferraris, S. Yasharpour, K. C. Kent Lloyd, R. Mirzayan and J. D. Diamond. Luminal glucose concentrations in the gut under normal conditions. Am. J. Physiol. 259; G822–G837 (1990).
- H. Bröndsted, H. Mörck and L. Hovgaard. Drug delivery studies in Caco-2 monolayers. III. Intestinal transport of various vasopressin analogues in the presence of lysophosphatidylcholine. Int. J. Pharm. 114, 151–157 (1995).
- H. Lennernäs. Gastrointestinal absorption mechanisms: A comparison between animal and human models. Eur J. Pharm. Sci. 2, 39–43 (1994).
- G. Holzheimer and D. Winne. Influence of distension on absorption and villous structure in rat jejunum. Am J. Physiol., 256, G188–G197 (1989).
- E.B. Chang and M.C. Rao. Intestinal water and electrolyte transport: mechanisms of physiological and adaptive responses. Physiology of the Gastrointestinal Tract, ed Johnson L.R., Raven Press, New York, 1994, pp 2027–2081.
- H. Lennernäs, U. Fagerholm, Y. Raab, B. Gerdin and R. Hällgren. Regional rectal perfusion, a new in vivo approach to study rectal drug absorption in man. Pharm. Res., 12, 426–432 (1994).
- S.A. Riley, M. Kim, F. Sutcliffe, M. Kapas, M. Rowland and L.A. Turnberg. Effects of a non-absorbable osmotic load on drug absorption in healthy volunteers. Br. J. Clin. Pharmacol. 34, 40–46 (1992).
- G.L. Amidon, H. Lennernäs, V.P. Shah and J. Crison. Theoretical considerations in the correlation of in vitro drug product dissolution and in vivo bioavailability: A basis for a biopharmaceutics drug classification. Pharm. Res., 12, 413–420 (1995).
- M.D. Levitt, A. Strocchi and D.G. Levitt. Human jejunal unstirred layer: evidence for extremely efficient luminal stirring. Am. J. Physiol., 262, G593–6 (1992).
- J.M. Diamond. Evolutionary design of intestinal nutrient absorption: Enough but not too much. News in Physiol. Sci., 6: 92–6 (1991).
- Does Fluid Flow Across the Intestinal Mucosa Affect Quantitative Oral Drug Absorption? Is It Time for a Reevaluation?
Volume 12, Issue 11 , pp 1573-1582
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- intestinal permeability
- water absorption
- solvent drag
- tight junctions
- paracellular absorption
- human permeability
- Industry Sectors
- Hans Lennernäs (1)
- Author Affiliations
- 1. Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, S-751 23, Uppsala, Sweden