Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalaprilat.

Abstract

1 The effect of induced water absorption on the intestinal permeability of antipyrine, atenolol and enalaprilat in the proximal jejunum was studied in eight healthy subjects with a regional intestinal perfusion technique. 2 The mean (± s.d.) net water flux changed from a secretory status of 1.2 ± 1.2 ml h-I cm-' to an absorptive status of -3.7 ± 3.5 ml h-' cm-' (P < 0.0025) on the introduction of a hypo-osmolar glucose-containing electrolyte solution. 3 The mean permeability values for the three drugs in the eight subjects were unchanged despite the increase in net water absorption (5.7 ± 3.0 to 7.0 ± 3.6 x 10-4 cm s-1 for antipyrine, 0.1 ± 0.2 to 0.2 ± 0.2 x 10-4 cm s-1 for atenolol and 0.3 ± 0.3 to 0.1 ± 0.2 x 10-4 cm S-1 for enalaprilat). One subject showed a large change in the permeability for antipyrine and atenolol in parallel with a large increase in water absorption, but enalaprilat was unaffected. 4 The luminal recovery of PEG 4000 was similar before (100 ± 4%) and during (101 ± 7%) induction of water absorption, which indicates that the barrier function of the intestine appears to be maintained during glucose-stimulated fluid absorption in man. 5 We conclude that induced net water absorption in man does not influence the paracellular permeability of hydrophilic drugs or drugs with high molecular weight to any significant extent. We suggest that this is because an important component of the net flux of water across the epithelial membrane may be transcellular and, in addition, the increased net absorptive flow of water could be due to a decreased secretory part of this flux.

The Talinolol Double-Peak Phenomenon Is Likely Caused by Presystemic Processing After Uptake from Gut Lumen

“…This excludes an uptake via watery channels (solvent drag phenomenon), which is not counteracted by P-gp (13,34). The paracellular absorption of talinolol seems to be low and not influenced by net water absorption, similar to the structurally related atenolol (35).…”

Modeling Gastrointestinal Drug Absorption Requires More In Vivo Biopharmaceutical Data: Experience from In Vivo Dissolution and Permeability Studies in Humans

“…The bioavailability of pro-drugs, such as valaciclovir and enalaprilate was 5 and 8 times higher, respectively, than that of aciclovir and enalapril themselves, due to transport by the intestinal transporter, hPepT1 [107,108]. The in vivo human jejunal P eff has been determined for four hPepT1 substrates: amoxicillin, cephalexin, enalapril and lisonipril [92,109,127]. These compounds have physicochemical properties that predict low passive diffusion across the human intestine [6,92].…”

“…On the other hand, the predicted permeability of drugs (C) that are transported via carrier-mediated processes deviate significantly from the experimental data, which is not surprising when human jejunum is compared with an in vitro model of colonic origin. Data originate from references [6,25,26,39,78,79,84,89,91,99,109,113,116,[125][126][127][128][129][130].…”

“…The proximal jejunum also has the largest surface area and is the site of the most active carrier-mediated transport in the gut [31,33,35,36]. Human in vivo jejunal permeability values for 43 compounds (31 drugs) have been determined over a period of 18 years and are given in Tables 3 and 4 [6,25,26,39,78,79,84,89,91,92,99,109,113,116,[124][125][126][127][128][129][130]. The majority (31 compounds) of these in vivo human permeability values have been determined in our laboratory at Uppsala University.…”

Enhancement of oral bioavailability of insulin in humans

“…Intestinal permeability can be determined experimentally by different methods such as single-pass perfusion technique in situ and regional jejunal perfusion technique in vivo (T. Z. Csaky, 1984;K.Ewe et al, 1994; H. Lennernäs et al, 1992Lennernäs et al, , 1994; R. Modigliani et al, 1973; D. C. Taylor et al, 1985).…”