Abstract
Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (±SD) fraction of phenazone absorbed calculated from perfusion data was 51 ± 12% (3 ml/min), 64 ± 19% (3 ml/min), and 42 ± 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 ± 16%, 51 ± 19%, and 38 ± 26%, respectively. The effective permeability of phenazone was 5.3 ± 2.5, 11 ± 6.8, and 11 ± 12 (x 104) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption. The absorption of phenazone and d-glucose were highly correlated, which was due partly to the mean residence time of the solution in the intestinal segment, but other factors such as variable mucosal surface area also seemed to be important. The new perfusion method was validated by the observed agreement found between absorption from the intestinal perfusate and the degree of absorption obtained by deconvolution of the plasma concentrations. Thus, the regional jejunal perfusion technique seems to have great potential for quantitative and mechanistic evaluations of drug absorption from the human intestine.
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REFERENCES
B. Borgström, A. Dahlqvist, G. Lundh, and J. Sjovall. Studies of intestinal digestion and absorption in human. J. Clin. Invest. 36:1521–1536 (1957).
G. E. Whalen, J. A. Harris, J. E. Geenen, and K. H. Soergel. Sodium and water absorption from the human small intestine. Gastroenterology 51:975–984 (1966).
R. L. Oberle, T.-S. Chen, C. Lloyd, J. L. Barnett, C. Owyang, J. Meyer, and G. L. Amidon. The influence of the interdigestive migrating myolectric complex on the gastric emptying of liquids. Gastroenterology 99:1275–1282 (1990).
G. Jobin, A. Cortot, J. Godbillon, M. Duval, J. P. Schoeller, J. Hirtz, and J. J. Bernier. Investigation of drug absorption from the gastrointestinal tract of man. I. Metoprolol in the stomach, duodenum and jejunum. Br. J. Clin. Pharmacol. 19:97S–105S (1985).
N. Vidon, D. Evard, J. Godbillon, M. Rongier, M. Duval, J. P. Schoeller, J. J. Bernier, and J. Hirtz. Investigation of drug absorption from the gastrointestinal tract of man. II. Metoprolol in the jejunum and ileum. Br. J. Clin. Pharmacol. 19:107S–112S (1985).
A. E. Merfeld, A. R. Mlodozeniec, M. A. Cortese, J. B. Rhodes, J. B. Dressman, and G. L. Amidon. The effect of pH and concentration on a-methyldopa absorption in man. J. Pharm. Pharmacol. 38:815–822 (1986).
L. Borgström, B. M. Kennedy, B. Nilsson, and B. Angelin. Relative absorption of the two enantiomers of terbutaline after duodenal administration. Eur. J. Clin. Pharmacol. 38:621–623 (1990).
K. H. Soergel. Flow measurements of test meals and fasting contents in the human small intestine. In L. Demling and R. Ottenjann (eds.), Gastrointestinal Motility, Georg Thieme, New York, 1971, pp. 81–92.
P. Kerlin, A. Zinsmeister, and S. Phillips. Relationship of motility to flow of contents in the human small intestine. Gastroenterology 82:701–706 (1982).
L. Knutson, B. Odlind, and R. Hällgren. A new technique for segmental jejunal perfusion in man. Am. J. Gastroenterol. 84:1278–1284 (1989).
L. Knutson, Ö. Ahrenstedt, B. Odlind, and R. Hällgren. The jejunal secretion of histamine is increased in active Crohn's disease. Gastroenterology 98:849–854 (1990).
Ö. Ahrenstedt, L. Knutson, B. Nilsson, K. Nilsson-Ekdahl, B. Odlind, and R. Hällgren. Enhanced local production of complement components in the small intestines in Crohn's disease. N. Engl. J. Med. 322:1345–1349 (1990).
A. C. Moffat, J. V. Jackson, M. S. Moss, and B. Widdop (eds.). In Clarke's Isolation and Identification of Drugs, Pharm. Soc. Great Britain, London, 1986, pp. 872–873.
M. Eichelbaum, H. R. Ochs, G. Roberts, and A. Somogyi. Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration. Arzheim.-Forsch./Drug Res. 32:575–578 (1982).
M. Danhof, A. van Zuilen, J. K. Boeijinga, and D. D. Breimer. Studies of the different metabolic pathways of antipyrine in man. Eur. J. Clin. Pharmacol. 21:433–441 (1982).
D. J. Greenblatt, M. K. Divoll, J. S. Harmatz, and R. I. Shader. Antipyrine absorption and disposition in the elderly. Pharmacology 36:125–133 (1988).
M. Eichelbaum and N. Spannbrucker. Rapid and sensitive method for the determination of antipyrine in biological fluids by high-pressure liquid chromatography. J. Chromatogr. 140:288–292 (1977).
M. Sarkar and H. T. Karnes. Comparison of solid-phase extraction and liquid-liquid extraction for high-performance liquid chromatographic analysis of antipyrine in plasma. J. Chromatogr. 434:324–326 (1988).
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).
D. W. Powell. In L. R. Johnson (ed.), Intestinal Water and Electrolyte Transport, Physiology of the Gastrointestinal Tract, Raven Press, New York, 1987, pp. 1267–1306.
D. Winne. The contribution of solvent drag to the intestinal absorption of the basic drugs aminopyrine and antipyrine from the jejunum of the rat. Naunyn-Schmiedeberg Arch. Pharmacol. 281:175–196 (1974).
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. Naunyn-Schmiedeberg Arch. Pharmacol. 281:197–217 (1974).
G. L. Amidon, J. Kou, R. L. Elliott, and E. N. Lightfoot. Analysis of models for determining intestinal wall permeabilities. J. Pharm. Sci. 69(12):1369–1373 (1980).
N. F. H. Ho, J. Y. Park, P. F. Ni, and W. I. Higuchi. Advancing quantitative and mechanistic approaches in interfacing gastrointestinal drug absorption studies in animals and humans. In W. Crouthamel and A. C. Sarapu (eds.), Animal Models for Oral Drug Delivery in Man; In Situ and in Vivo Approaches, American Pharmaceutical Association, Washington, DC, 1983, pp. 27–106.
K. Iga, Y. Ogawa, T. Yashiki, and T. Shimamoto. Estimation of drug absorption rates using a deconvolution method with non-equal sampling times. J. Pharmacokin. Biopharm. 14:213–225 (1986).
G. L. Amidon, P. J. Sinko, and D. Fleisher. Estimating human oral fraction dose absorbed: A correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm. Res. 10:651–654 (1988).
P. Artursson and J. Karlsson. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Comm. 3:880–885 (1991).
D. Winn. Role of blood flow in intestinal permeation. In T. Z. Csáky (ed.), Pharmacology of Intestinal Permeation II, Springer-Verlag, Berlin, 1984, pp. 301–347.
M. D. Levitt, J. K. Furne, A. Strocchi, B. W. Anderson, and D. G. Levitt. Physiological measurements of luminal stirring in the dog and human small bowel. J. Clin. Invest. 86:1540–1547 (1990).
B. W. Anderson, A. S. Levine, D. G. Levitt, J. M. Kneip, and M. D. Levitt. Physiological measurement of luminal stirring in perfused rat jejunum. Am. J. Physiol. 254:G843–G848 (1988).
W. H. Karasov and J. M. Diamond. Adaptive regulation of sugar and amino acid transport by vertebrate intestine. Am. J. Physiol. 245:G443–G462 (1983).
J. M. Diamond. Evolutionary design of intestinal nutrient absorption: Enough but not too much. NIPS 6:92–96 (1991).
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Lennernäs, H., Ahrenstedt, Ö., Hällgren, R. et al. Regional Jejunal Perfusion, a New in Vivo Approach to Study Oral Drug Absorption in Man. Pharm Res 9, 1243–1251 (1992). https://doi.org/10.1023/A:1015888813741
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DOI: https://doi.org/10.1023/A:1015888813741