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Perfusion experiments, intestinal

In practice, estimation of Laq requires information on the rate of solute removal at the membrane since aqueous resistance is calculated from experimental data defining the solute concentration profile across this barrier [7], Mean /.aq values calculated from the product of aqueous diffusivity (at body temperature) and aqueous resistance obtained from human and animal intestinal perfusion experiments in situ are in the range of 100-900 pm, compared to lumenal radii of 0.2 cm (rat) and 1 cm (human). These estimates will necessarily be a function of perfusion flow rate and choice of solute. The lower Laq estimated in vivo is rationalized by better mixing within the lumen in the vicinity of the mucosal membrane [6],... [Pg.170]

Figure 2.5 Mass balance model for intestinal perfusion experiments at steady state (Adapted from Johnson and Amidon [129]). Figure 2.5 Mass balance model for intestinal perfusion experiments at steady state (Adapted from Johnson and Amidon [129]).
The choice of flow rates in perfusion experiments is an important consideration as it may affect hydrodynamics [35], ABL thickness [30], intestinal radius [34], intestinal surface area [45], and time to reach steady-state conditions [32], all of which can impact on Peff estimates. The intestinal radius has implications for the estimation of the permeability coefficient. The most widely used estimate for the rat intestinal radius is 0.18 cm [34], These authors found that there was a small change in intra-luminal pressure with an increase in flow... [Pg.48]

To facilitate a standardisation of inter-laboratory results of permeability, it is now common practice to include a range of model drugs as internal standards in initial validation (i.e. method suitability) of intestinal perfusion techniques [116]. A list of 20 model drugs has been reported by the FDA for the standardisation of the in situ intestinal perfusion experiment, whereas six drugs are recommended for human studies. Once the method has been... [Pg.63]

Note Data represent the mean S.E. (n = 3). MW, molecular weight P0/w, octanol-to-water partition coefficient CLapp, apparent membrane permeability clearance SI, midgut area of the small intestine NA, not available or applicable. Absorption was evaluated in our laboratory using the closed loop of the rat intestine in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for riboflavin and L-camitine and 30 min for the others. For those that are transported by carriers in part (riboflavin and glycerol in both colon and SI, and L-carnitine, 5-fluorouracil, and cephradine in SI), absorption was evaluated at higher concentrations where the contribution of carrier-mediated transport is negligible. Values of P0/w were obtained from a report by Leo et al. [30] except for that of D-xylose, which was determined in our laboratory. a Data by single-pass perfusion experiments. b Unpublished data from our laboratory. [Pg.85]

The presence of folds and villi structures on the surface area is not taken into account for the in vivo effective intestinal membrane permeability (Pefr when extrapolated from a perfusion experiment, a smooth tube is usually assumed). In humans, the fold expansion (FE) of the surface area is about threefold, and villi expansion (VE) is about 10-fold [7]. In the case of high epithelial membrane permeability (Pep) absorption occurs at the top of the villi before diffusing down the villi channels, whereas low Pep compound may diffuse down the villi channels to the crypts (Figure 6.1). Therefore, accessibility (Acc) to the surface depends on Pep and diffusion coefficient [7, 8]. The effective membrane permeability can be expressed as ... [Pg.119]

Evidence from rats suggests that apoE is synthesized almost exclusively in the liver (M31, W19). Perfusion experiments show that the liver produces discoid nascent HDL particles which are rich in apoE, and which also contain apoA-I (Dl, D2, F8, H3, H5, Kll, M31). ApoE is not found in chylomicrons of intestinal lymph, and its presence in chylomicrons in blood suggests that a transfer from nascent HDL to chylomicrons occurs (G28, 14). [Pg.248]

The concentrations of the compound are determined using appropriate analytical methods for the respective candidate compound in the perfusate at the end of the perfusion experiment, plasma, bile and hepatic tissue. From the data the site of intestinal absorption using different perfused intestinal segments in separate experiments as well as the degree of hepatobiliary elimination can be estimated. [Pg.487]

Appropriate analytical methods with sufficient sensitivity are used for detection of the candidate compound in the perfusate, plasma, bile and liver tissue. From the total amount of the candidate compound in the perfusate of the respective intestinal segment at the end of the perfusion experiment in relation to the total added amount of compound at time 0, the total enteral absorption rate can be estimated. The decline in the concentration of the candidate compound in the perfusate is a measure of the enteral absorption, the uptake, metabolism and elimination of the compound by the liver. The concentration in the plasma is a measure of the bioavailability. The appearance of the candidate compound in the bile is a measure of the hepatobiliary elimination of the compound. The tissue level of the candidate compound is a measure of the uptake and... [Pg.487]

In recent experiments, we have employed two approaches to examine specific aspects of zinc absorption. The Isolated, vascularly perfused rat intestine has been employed to examine absorption at the organ level. Isolated brush border membranes from rat intestine have been used to study the transfer of zinc across the intestinal surface. [Pg.236]

Male rats used for the perfusion experiments were maintained under established conditions and were fasted 16-24 hours prior to surgery as previously described (35). In the first series of studies the luminal perfusate was at pH 4.2. This perfusate consisted of M199 tissue culture medium which contained a variety of amino acids, vitamins and minerals plus glucose. The perfusate was supplemented (at 110 umolar) with L-histidine HCl, L-cysteine, L-methionine, L-tryptophan, 2-picolinic acid, citric acid, or reduced glutathione. The mixture was Infused into the lumen at 0.39 ml per min for 20 min and 0.10 ml per min for the final 40 min of the experiments. The small Intestine was then removed and mucosal... [Pg.236]

Studies in which Stevia extracts or solutions of pure stevioside have been injected in the animals or were used in perfusion experiments of organs, are considered as not relevant for the use of Stevia or stevioside as food. As indicated above the sweet components of Stevia used in low concentrations, are not taken up in the human body and are not metabolised by the digestive enzymes from the gastro-intestinal tract. [Pg.313]

Clinical studies of Peff, secretion, and metabolism of various compounds such as drugs, environmental pollutants, and nutrients are rarely performed in vivo in humans even if experimental techniques are available (Figures 9.2-9.4) [3, 11, 13, 16, 17, 24—31]. Direct measurements of compound transport and metabolism in mesenteric and portal veins in humans are not possible for obvious reasons. Perfusion techniques, however, present great possibilities to measure intestinal processes. Over the past 70 years, different in vivo intestinal perfusion techniques have been developed and the importance of this work has been clearly demonstrated [3, 5, 6,11,13-16, 25-31]. The fundamental principle of an in vivo intestinal perfusion experiment is that Peff is calculated from the rate at which the compound disappears... [Pg.190]

With the difficulties associated with accurate estimation of permeability based only on physicochemical properties, a variety of methods of measuring permeability have been developed and used, among which are (l)cul-tured monolayer cell systems, such as Caco-2 or MDCK ( 2 diffusion cell systems that use small sections of intestinal mucosa between two chambers (3) in situ intestinal perfusion experiments performed in anesthetized animals such as rats and (4)intestinal perfusion studies performed in humans (40,54-62). All of these methods offer opportunities to study transport of drug across biological membranes under well-controlledconditions. Caco-2 mono-layer systems in particular have become increasingly commonly used in recent years and human intestinal perfusion methods are also becoming more commonly available. Correlations between Caco-2 permeability and absorption in humans have been developed in several laboratories (63-72). As shown in Fig. [Pg.659]

Intestinal Perfusion Experiments. Hydrolysate solutions for use in the perfused Intestine experiments were prepared by concentrating the pronase hydrolysates approximately two-fold in a rotary evaporator at 60 C (to inactivate pronase, 24) and mixing the equivalent of 157.5 mg (untreated zeln), 289.2 mg (Ca(0H)2-treated zein) or 150.0 mg (NaOH-treated zein) with 0.05M HEPES (Calbio-chem-Behring Corp., LaJolla, CA) buffer (pH 8.0). The final solutions had a pH of 8.10 0.05. [Pg.192]

A summary of the results from the perfused intestine experiment is shown in Figure 8. The results are expressed as the mean uptake of all the measured amino acids for the three zein hydrolysates. The results from this series clearly show that uptake has been reduced by both soda- and lime-treatments of zein, which is also consistent with the results of the pronase study which show that both calcium hydroxide and sodium hydroxide treatments decrease digestibility. However, it is not clear why the results for Ca(0H)2 treated zein are different for the everted sac and perfusion experiments, hut this may be related to the better viability of the in vivo perfusion technique. [Pg.200]

The effort to understand the interrelationship of physical forces and cellular activity in the transport of salt solutions was advanced considerably by the experiments of Curran and Solomon [5] on the rat small intestine. These workers perfused the intestinal lumen of the rat with solutions all isotonic to plasma but with varying NaCl concentration. They measured both the solute flux and volume flow out of the lumen and their results are plotted in Fig. 3. These data are taken as strong evidence for the primacy of solute flux as the determinant of transepithelial water flow. This view was confirmed in experiments by Windhager et al. (6) in which the epithelium under investigation was the renal proximal tubule of the amphibian, Necturus. [Pg.312]

The formation of estrogen glucoaduronates has been demonstrated in vitro with liver (Crepy, 1946) and with intestine (Lchtinen el aZ., 1958a, b) as well as after perfusion of intestinal loops (Diczfalusy et oZ., 196ld Schiirholz and Staib, 1961). Special interest attaches to the experiments of... [Pg.316]

Intestinal excretion is an important mechanism in the elimination of flavonoid conjugates [82-84]. This is likely mediated by the multidrug resistance-associated protein (MRP) pumps. MRPs actively export conjugated metabolites out of the small intestine back into the intestinal lumen and so prevent or reduce systemic circulation [85]. An experiment using cultured Caco-2 cells showed that two metabolites of epicatechin were excreted on the apical side of the cells. Their elimination has been attributed to MRP-2, as efflux was significantly reduced by a competitive MRP-2 inhibitor [86]. Conversely, intestinal perfusion experiments with catechin indicate that catechin metabolites are not substrates for these transport proteins [49]. [Pg.430]

The advantages of the in situ techniques include an intact blood supply multiple samples may be taken, thus enabling kinetic studies to be performed. A fundamental point regarding the in situ intestinal perfusion method is that the rat model has been demonstrated to correlate with in vivo human data [46 19], Amidon et al. [36] have demonstrated that it can be used to predict absorption for both passive and carrier-mediated substrates. However, the intestinal luminal concentrations used in rat experiments should reflect adequately scaled and clinically relevant concentrations to ensure appropriate permeability determinations [50], There are limitations of the in situ rat perfusion models. The assumption involved in derivation of these models that all drug passes into portal vein, that is drug disappearance reflects drug absorption, may not be valid in some circumstances as discussed below. [Pg.49]


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