Summary
Using the isolated vascularly fluorocarbon emulsion perfused rat small intestine some factors which determine the extent of the intestinal glucuronidation of 1-naphthol to 1-naphthol-β-d-glucuronide were studied. Increasing the luminal 1-naphthol concentration resulted in a concomitant increase in the 1-naphthol appearance in the vascular perfusate. In contrast, the total appearance of 1-naphthol-β-d-glucuronide increased less than proportional to the increase in the luminal 1-naphthol concentration. About 88% of the total amount of 1-naphthol-β-d-glucuronide excreted was released into the vascular perfusate. The capacity-limited intestinal glucuronide efflux is most likely due to saturation of the excretory mechanism for 1-naphthol-β-d-glucuronide. Decreasing the vascular flow rate influenced both the appearance of 1-naphthol and 1-naphtol-β-d-glucuronide in the vascular perfusate, whereas the appearance of 1-naphthol-β-d-glucuronide in the luminal perfusate was essentially flow-independent. A noradrenaline-induced change in the haemodynamic state of the vascular bed (with the total flow kept constant) resulted in a marked decrease in the 1-naphthol vascular concentration. The vascular 1-naphthol-β-d-glucuronide concentration was only slightly affected. These results indicate that changes in blood flow and blood flow distribution within the intestinal wall can affect the extent of presystemic intestinal metabolism by interfering with the absorption of the parent compound and the efflux of formed conjugates. These parameters can be of paramount importance for causing variable intestinal first-pass effects of drugs in vivo.
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References
Angus PW, Mihaly GW, Morgan DJ, Smallwood RA (1988) Synergistic effects of hypoxia and fasting on harmol elimination in the isolated perfused rat liver. Biochem Pharmacol 37:1207–1212
Aw TY, Jones DP (1982) Secondary bioenergetic hypoxia. Inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low oxygen concentrations. J Biol Chem 257:8997–9004
Barr WH, Riegelman S (1970) Intestinal drug absorption and metabolism I and II. J Pharmacol Sci 59:154–168
Bock KW, Winne D (1975) Glucuronidation of 1-naphthol in the rat intestinal loop. Biochem Pharmacol 24:859–862
Borm AJP, Frankhuijzen-Sierevogel JC, Weller EBC, Noordhoek J (1985) Absorption and metabolism of hexamethylmelamine and pentamethylmelamine in rat everted perfused gut segments: Correlation with in-vivo data. J Pharm Pharmacol 37:629–636
Chou CC, Grassmick B (1978) Motility and blood flow distribution within the wall of the gastrointestinal tract. Am J Physiol 235:H34-H39
Chou CC, Kvietys PR (1981) Physiological alterations in gastrointestinal blood flow. In: Granger N, Bulkley GB (eds) Measurement of blood flow; applications to the splanchnic circulation. Williams and Wilkins, Baltimore, pp 477–509
De Vries MH, Hofman GA, Koster ASj, Noordhoek J (1989) Systemic intestinal metabolism of 1-naphthol. A study in the vascularly perfused rat small intestine. Drug Metab Dispos (in press)
Dresel P, Wallentin I (1966) Effects of sympathetic vasoconstrictor fibres, noradrenaline and vasopressin on the intestinal vascular resistance during constant blood flow or blood pressure. Acta Physiol Scand 66:427–436
Folkow B, Lewis DH, Lundgren O, Mellander S, Wallentin I (1964) The effect of sympathetic vasoconstrictor fibres on the distribution of capillary blood flow in the intestine. Acta Physiol Scand 61:458–466
George CF (1981) Drug metabolism in the gastrointestinal mucosa. Clin Pharmacokin 6:259–274
Geyer RP (1975) “Bloodless” rats through the use of artificial blood substitutes. Federation Proc 34:1499–1505
Granger DN, Richardson P, Kvietys R, Mortillaro NA (1980) Intestinal blood flow. Gastroenterology 78:837–863
Greenway CV, Scott GD, Zink J (1976) Sites of autoregulatory escape of blood flow in the mesenteric vascular bed. J Physiol 259:1–12
Hartmann F, Vieillard-Baron D, Heinrich R (1984) Isolated perfusion of the small intestine using perfluorotributylamine as artificial oxygen carrier. Adv Exp Med Biol 180:711–720
Hulten L, Lindhagen J, Lundgren O (1977) Sympathetic nervous control of intramural blood flow in the feline and human intestines. Gastroenterology 72:41–48
Josting D, Winne D, Bock KW (1976) Glucuronidation of paracetamol, morphine and 1-naphthol in the rat intestinal loop. Biochem Pharmacol 25:613–616
Koster ASj, Noordhoek J (1983) Glucuronidation in isolated perfused rat intestinal segments after mucosal and serosal administration of 1-naphthol. J Pharmacol Exp Ther 226:533–538
Koster ASj, Meewisse CPJ, Noordhoek J (1984) Glucuronidation in rat intestinal epithelial cells. Dependence on glucose supply and resistance to inhibition by ethanol and fasting. Arch Toxicol 55:123–126
Koster ASj (1985) Intestinal glucuronidation: in vivo and in vitro model systems. In: Bock KW, Matern S, Gerok W (eds) Advances in glucuronide conjugation. MTP Press, Lancaster, pp 177–195
Koster H, Halsema I, Scholtens E, Pang KS, Mulder GJ (1982) Kinetics of sulfation and glucuronidation of harmol in the perfused rat liver preparation. Disappearance of aberrancies in glucuronidation kinetics by inhibition of sulfation. Biochem Pharmacol 31:3023–3028
Lewis LD, Fordtran JS (1975) Effect of perfusion rate on absorption, surface area, unstirred water layer thickness, permeability and intraluminal pressure in the rat ileum in vivo. Gastroenterology 86:1509–1516
Miyazaki K, Sunada K, Iseki K, Arita T (1986) Simultaneous vascular and luminal perfusion of rat small intestine. Chem Pharmacol Bull 34:3830–3835
Noordhoek J (1987) Systemic and presystemic drug metabolism in intestinal epithelium. In: Breimer DD, Speiser P (eds) Topics in pharmaceutical sciences 1987. Elsevier Science Publishers, Amsterdam, pp 457–469
Oesch M, Sahli M (1974) Zur gaschromatographischen Bestimmung von Phenol, Coffein, Antipyrin und Dimethylaminoantipyrin in pharmazeutischen Spezialitäten. Pharmacol Acta Helv 49: 317–321
Pekas JC (1971) Naphthol metabolism: glucuronide conjugation and transport by the rat intestine in vitro. Toxicol Appl Pharmacol 29:404–419
Schulz R, Winne D (1987) Relationship between antipyrine absorption and blood flow rate in rat jejunum, ileum and colon. Naunyn-Schmiedeberg's Arch Pharmacol 335:97–102
Sund RB, Lauterbach F (1986) Drug metabolism and metabolite transport in the small and large intestine: Experiments with 1-naphthol and phenolphtalein by luminal and contraluminal administration in the isolated guinea pig mucosa. Acta Pharmacol Toxicol 58:74–83
Svanvik J (1973) Musocal blood circulation and its influence on passive absorption in the small intestine. Acta Physiol Scand Suppl 385:1–44
Windmueller HG, Spaeth AE, Ganote CE (1970) Vascular perfusion of isolated rat gut. Am J Physiol 218:197–204
Winne D (1979) Influence of blood flow on intestinal absorption of drugs and nutrients. Pharmacol Ther 6:339–393
Winne D (1984) Unstirred layer as a diffusion barrier in vitro and in vivo. In: Skadhauge E, Heintze K (eds) Intestinal absorption and secretion. MTP-Press, Lancaster, pp 21–38
Wollenberg P, Ullrich V, Rummel W (1983) Conjugation of 1-naphthol and transport of 1-naphthol-conjugates in the vascularly perfused small intestine of the mouse. Biochem Pharmacol 32:2103–2107
Wollenberg P, Rummel W (1984) Vectorial release of sulfoconjugates in the vascularly perfused mouse small intestine. Biochem Pharmacol 33:205–208
Wollenberg P, Rummel W (1985) Influence of phosphate, sulfonic and sulfamic acids on sulfoconjugate release in the vascularly perfused mouse small intestine. Naunyn-Schmiedeberg's Arch Pharmacol 329:195–200
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de Vries, M.H., Hofman, G.A., Koster, A.S. et al. Absorption and presystemic glucuronidation of 1-naphthol in the vascularly fluorocarbon emulsion perfused rat small intestine. Naunyn-Schmiedeberg's Arch Pharmacol 340, 239–245 (1989). https://doi.org/10.1007/BF00168975
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DOI: https://doi.org/10.1007/BF00168975