M. Merino

Intestinal absorption of zearalenone and in vitro study of non-nutritive sorbent materials

Abstract Zearalenone is a mycotoxin produced by several members of the genus Fusarium that elicits oestrogenic effects on mammalian reproductive systems. Methods for an effective detoxification of contaminated feedstuffs are not currently available, but one of the new approaches to the problem is the addition of non-nutritive sorptive materials to the diets of animals in order to reduce gastrointestinal absorption of mycotoxins. The objectives of this study were to examine the intestinal absorption of zearalenone, to evaluate several sorbent materials for zearalenone affinity in vitro, and to select a potentially efficacious candidate for protection against zearalenone intoxication. In situ results obtained showed that the absorption of zearalenone in the rat small intestine follows first-order kinetics, with an absorption rate constant ka, of 9.27 ± (0.69)/h. In vitro adsorption tests of zearalenone by selected materials showed that cholestyramine was the best adsorbent, followed in decreasing order by crospovidone, montmorillonite, bentonite, sepiolite and magnesium trisilicate. The Freundlich isotherm showed a better fit than the Langmuir isotherm. This could suggest the existence of a heterogeneous sorbent surface, the existence of different adsorption mechanisms or both. Results demonstrated that crospovidone was able to adsorb 313.7 μg zearalenone/g adsorbent, whereas montmorillonite, bentonite, sepiolite and magnesium trisilicate were able to adsorb 192.2, 112.4, 74.37 and 22.61 μg zearalenone/g adsorbent, respectively. Cholestyramine adsorption parameters were above these levels.

Intestinal absorption kinetics of amiodarone in rat small intestine

Amiodarone is a widely used antiarrhythmic agent with highly variable therapeutic effects. These seem to be related, at least in part, to the pharmacokinetics of the drug and particularly to some features of its gastrointestinal absorption process. The drug exhibits physico‐chemical properties highly suitable for diffusion across lipophilic absorbing membranes, but its low aqueous solubility can act as the rate limiting step for absorption, making the process erratic and variable. In order to gain an insight into the intestinal absorption mechanism of the drug and detect possible non‐linearities, a series of experiments using a classical rat gut in situ preparation were carried out with three amiodarone hydrochloride solutions (10, 75, and 200 μg mL−1). A synthetic non‐ionic surfactant, polysorbate 80, at supramicellar concentration (2 mM) was used as the drug solubilizer. Amiodarone was assayed in biological samples by HPLC using a rapid, sensitive technique that was validated. The amiodarone first‐order absorption rate constants obtained in these conditions were similar. No significant differences between ka values were found. Amiodarone absorption was clearly identified as a passive diffusion process.

Effects of polysorbate 80 on amiodarone intestinal absorption in the rat

Abstract Amiodarone is a widely used anti-arrhythmic agent which shows physico-chemical properties that are highly suitable for diffusion across lipophilic absorbing membranes, however,.its low aqueous solubility could represent the rate-limiting step for absorption, making it erratic and variable. In a previous paper, the influence of an anionic surfactant (sodium lauryl sulphate) at variable supramicellar concentrations was studied. The absorption rate constants of amiodarone decreased as the surfactant concentration increased, and absorption was unusually fast at lower surfactant concentrations. The previously proposed equations for interpreting the relationships between the amiodarone absorption rate constant and sodium lauryl sulphate concentration in the intestinal lumen are extended here to the absorption of the drug in the presence of a non-ionic surfactant (polysorbate 80) at different supramicellar concentrations (from 0.4 to 80 mM). In the same way, a modification of the previously reported equations for quantifying the absorption of micellized drug through the intestinal membrane is described. This modification has been applied to the results obtained for both surfactants, but does not improve the previously postulated biophysical model.

Effects of surfactants on amiodarone intestinal absorption. I. Sodium laurylsulfate.

Amiodarone is a widely used antiarrhythmic agent with high variability in therapeutic effects, which appears to be related, at least in part, to its pharmacokinetics, and in particular, gastrointestinal absorption. The drug exhibits physico-chemical properties highly suitable for diffusion across lipophilic absorbing membranes but its low aqueous solubility can act as the rate limiting step for absorption, making it erratic and variable. In studying the intestinal absorption mechanism of amiodarone, a series of experiments using a rat gut in situ preparation was performed in the presence of a synthetic anionic surfactant, as a drug solubilizer, i.e., sodium laurylsulfate, at variable supramicellar concentrations (from 2.6 to 104 mM). Absorption rate constants of amiodarone decreased as surfactant concentration increased, the absorption being unusually fast at lower surfactant concentrations. Equations were developed to evaluate the relationship between absorption rate constant and surfactant concentration in the intestinal luminal fluid.

Evidence of competitive inhibition of methotrexate absorption by leucovorin calcium in rat small intestine

Abstract The effect of leucovorin calcium on the intestinal absorption of methotrexate in rat small intestine was investigated using an in situ rat gut technique. First, the kinetic absorption in situ parameters for methotrexate in solution were obtained: V m =21.54 (±2.22) μ M/h; K m =10.51 (±1.08) μ M; k a =0.26 (±0.03) h −1 and AIC=−188.63. The inhibitory effect of leucovorin calcium in methotrexate intestinal absorption has been investigated by perfusing of 10 μ M methotrexate isotonic solutions containing increasing concentrations of leucovorin calcium (10–500 μ M), and the remaining concentrations of both compounds were measured. A competitive inhibition of methotrexate absorption was detected: the apparent absorption rate constant of the drug decreased as the initial leucovorin calcium concentration increased. Higher leucovorin calcium concentrations, however, did not completely abolish the absorption of the drug (at 500 μ M of leucovorin calcium, only 84% inhibition was observed). Apparent parameters characterizing the absorption of leucovorin calcium in the presence of methotrexate 10 μ M were: V mi =14.70 (±1.74) μ M; K mi =9.43 (±1.59) μ M; k ai =0.28 (±0.02) h −1 ; AIC=−191.53). We can concluded that methotrexate and leucovorin calcium compete for the same intestinal carrier system. This means that since leucovorin calcium, because of its ready conversion to other tetrahydrofolic derivatives (McEvoy, 1996. AHFS Drug Information, Bethesda, MD, pp. 751–758), is administered together with methotrexate in order to prevent the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists, using high leucovorin calcium concentrations, when the urine excretion is decreased, could prevent intestinal drug reabsorption and the drug could then be excreted in the feces, thereby decreasing the risk of poisoning.

Evidence of competitive inhibition for the intestinal absorption of baclofen by phenylalanine

Abstract Previous studies showed that the absorption of the antispastic drug baclofen, in the rat middle intestine, is inhibited by β-alanine, γ-aminobutyric acid (GABA) and leucine. It was concluded that baclofen intestinal transport was mediated, at least in part, by the β-, γ- and α-amino acid carriers. We therefore focused our next studies on the analysis of the possible inhibition of drug absorption by an aromatic α-amino acid model compound, phenylalanine. An in situ study in the rat small intestine was undertaken in order to evaluate the effect of phenylalanine on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with initial phenylalanine concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease as the phenylalanine concentration increases, with a limiting value of 0.33 h−1 ( ±0.06). Complete competitive inhibition in the presence of a second component could define the interaction phenomena between these substances, since higher concentrations of phenylalanine do not completely abolish baclofen absorption. We have completed the studies using phenylalanine and GABA together as inhibitors of drug absorption. An isotonic perfusion solution of 0.5 mM baclofen in the presence of 100 mM phenylalanine and 100 mM GABA was perfused. Under these conditions the absorption rate pseudoconstant of baclofen decreases until 0.16 h−1 (±0.06).