Intestinal permeation of nonquaternary amines: a study with telenzepine and pirenzepine in the isolated mucosa of guinea pig jejunum and colon.
Previous studies which demonstrated an intestinal secretion of quaternary ammonium compounds in the jejunum were extended to nonquaternary amines. Telenzepine and pirenzepine, two structurally similar compounds differing in lipid solubility, were administered either to the lumen or blood side of isolated mucosae of guinea pig jejunum and colon mounted in a flux chamber. Transepithelial permeation of both drugs from blood to lumen side was 3.2 to 18 times higher than in the reverse, absorptive direction. The indicated net secretion was highest with telenzepine in the colon. At 7 degrees C transepithelial permeation was restricted to paracellular shunt fluxes. In the colon, the highest cellular concentrations were observed after blood side administration of telenzepine and pirenzepine (500 and 150% of that of the incubation solution). At 7 degrees C these values were reduced to 1 of 5 and 1 of 8 of the values at 37 degrees C. At pH 6.6, 7.4 or 8.2, no differences in the colonic secretion of telenzepine were seen; cellular concentration increased with increasing pH only after luminal administration. Under all conditions, the colon acidified the luminal solution by roughly 0.4 pH units. Phenoxybenzamine, shown previously to inhibit the jejunal secretion of quaternary ammonium compounds, inhibited the secretion of pirenzepine and telenzepine in both gut segments, but did not affect blood-to-lumen permeation of N-methylscopolamine in the colon. In addition, phenoxybenzamine reduced the cellular content in the colon but had little or no effect on pirenzepine or telenzepine content in the jejunum. The results are consistent with a model in which the nonquaternary amines are secreted in the jejunum by two serial transport steps specific for the base cations; an additional diffusion of the free bases is of importance in the basolateral membrane. In the colon, carrier-mediated influx increases with lipophilicity of the base cations, whereas efflux across the brush border is limited to diffusion of the free bases; concomitant luminal acidification and formation of base cations maintains the diffusion gradient.
Department of Pharmacology and Toxicology, Ruhr-University, Bochum, Federal Republic of Germany.
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Lauterbach
D000818:Animals; D001692:Biological Transport; D003106:Colon / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D019832:N-Methylscopolamine; D010539:Permeability; D010643:Phenoxybenzamine / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics; D013696:Temperature
D012602:Scopolamine Derivatives; C046338:telenzepine; D010643:Phenoxybenzamine; D010890:Pirenzepine; D011092:Polyethylene Glycols; D019832:N-Methylscopolamine