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-1 cm-1 to an absorptive status of -3.7 +/- 3.5 ml h-1 cm-1 (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 × 10(-4) cm s-1 for antipyrine, 0.1 +/- 0.2 to 0.2 +/- 0.2 × 10(-4) cm s-1 for atenolol and 0.3 +/- 0.3 to 0.1 +/- 0.2 × 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.(ABSTRACT TRUNCATED AT 250 WORDS)