Intestinal absorption of 250ml water as recommended for oral drug administration in pharmacokinetic studies in man

Background: In fasting healthy human subjects, we have shown that the mean water volume in the small intestine was only ∼100 mL scattered to 4-8 pockets although 150 ml were drunken 7, 4 and 1 h before evaluation (Schiller et al., Aliment Pharmacol Ther 2005). Therefore, we measured the intestinal fate of water which is recommended by FDA and EMA for oral drug administration studies and evaluated influences on extent and rate of absorption of suitable probe drugs. Methods: Intestinal kinetics of water and oral absorption of acetaminophen and amoxicillin (both 500 mg, LC-MS analysis) dissolved both in 240 ml non-caloric table water and 250 mg caloric water (∼100 kcal sucrose, iso-osmolar) for swallowing were evaluated in a randomized, controlled, cross-over study (7 days wash-out) in 4 female and 10 male healthy subjects (19-34 years, BMI 19.527 kg/m2). Area under the water volume curve (AUVC) stomach, proximal (duodenum, jejunum), ileum and colon was quantified up to 120 min (5 min intervals) using water-sensitive T2-weighted 1.5 T magnetic resonance imaging and manual volumetric analysis. Results: The total intestinal water measured immediately after drug administration (∼330 ml) disappeared from gut lumen within 2 h whereby the volume in the ileum and colon remained basically unchanged. Non-caloric water was emptied from the stomach in <60 min without increasing the volumes in the proximal intestine markedly thus driving the rate of acetaminophen and amoxicillin absorption. Caloric water was emptied more slowly, increased the volume in the upper intestine for about 30 min and delayed absorption of the probe drugs. Furthermore, we found preliminary evidence for water secretion both after ingestion of 250 ml non-caloric and caloric water. Conclusions: Water recommended for swallowing drugs in pharmacokinetic studies is rapidly absorbed from the proximal intestine in dependence on caloric load. This may in turn influence concentration dependent uptake processes at the sites of absorption of immediately releasing drugs.