The influence of perfusion rate on salicylate absorption in the rat

Abstract

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

Estimation of absorption parameters from the non-steady-state phase in the rat gut perfusion model

“…Ho et al (1983) showed that for progesterone the P ap p increased with flow rate, while in contrast, no effect was observed in the case of hydrocortisone. With the ionizable compounds, chlorothiazide and salicylic acid, the P app of the former increased with fluid flow while for the latter it appeared to decrease (O'Driscoll 1983). It was suggested that these effects were linked to pH changes affecting the degree of ionization (O'Driscoll & Corrigan 1983).…”

“…Alternative mass transport models, which make different assumptions with respect to the experimental convection and diffusion conditions, including laminar flow, plug flow or perfect mixing tank models, may also be applied to determine the permeability coefficient . In practice different authors have used different perfusion fluid flow rates ranging from 0.1 to 4.0 mL min ¡1 O'Driscoll & Corrigan 1983; O'Reilly et al 1994; Lane et al 1996).…”

“…With the ionizable compounds, chlorothiazide and salicylic acid, the P app of the former increased with fluid flow while for the latter it appeared to decrease (O'Driscoll 1983). It was suggested that these effects were linked to pH changes affecting the degree of ionization (O'Driscoll & Corrigan 1983). More recently increased fluid flow, resulting in increased pressure, was shown to increase the intestinal diameter and this effect was implicated in the change in absorption observed Fihn et al 2000).…”

“…Equation 1 allows calculation of the P app in the steady state, which is when the concentration in the effluent becomes constant. The actual concentration vs time profile is in practice sigmoid in shape Amidon et al 1980;O'Driscoll & Corrigan 1983) and the time to reach steady state decreases with increased fluid flow rate. To estimate the permeability of poorly absorbed drugs, low flow rates may be employed to detect a concentration drop and consequently the time to reach the steady state may be prolonged and difficult to define.…”