Chlorothiazide in solution was administered at four dose levels to three healthy male volunteers under controlled conditions. Excretion data indicated that the drug was poorly absorbed from the gastrointestinal tract. The 24 h recovery of the drug from urine fell from 33 to 6% as the dose was increased from 0·21 to 1·75 g per 70 kg of body weight. The cumulative amount of sodium excreted could be correlated with the cumulative amount of drug excreted, rather than with the dose administered. The electrolyte excretion response intensity could also be correlated with the amount of drug excreted. There was a poor linear relationship between response intensity and drug excretion rate. After higher doses the data suggested that the response was in the non‐linear section of the dose response curve.
The rate of flow of a drug solution down the gastrointestinal tract will influence the residence time at the absorption site and the permeability coefficient governing mass transport across the intestinal wall. Komiya et al (1980) examined the effect of fluid flow on the intestinal absorption of a number of steroids using the in-situ through-and-through rat intestinal perfusion technique. Their steady state results followed the physical model predictions described by:where C(I)/C(o) is the fraction of steroid remaining in the intestinal lumen of length 1, r is the effective radius, Q is the fluid flow rate and Papp is the apparent permeability coefficient. Furthermore the relationship between Papp and Q was expressed by Papp 0~ Qa with the coefficient a varying from zero, for membrane controlled solutes, to 0.44 for solutes the absorption of which was aqueous boundary layer controlled. These results together with those of Amidon et a1 (1980), who also used a non-dissociating solute, suggesting that gastrointestinal flow in the rat perfusion technique can be approximated by laminar flow in a cylindrical tube.Using a similar experimental procedure, we have examined the absorption of salicylic acid, a dissociating solute, under varying flow conditions.
Methods
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