J.M. Plá-Delfina

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.

Studies on the reliability of a bihyperbolic functional absorption model. I. Ring-substituted anilines

The present study reviews and checks the rearranged master lines of the functional bihyperbolic absorption model proposed by Plá-Delfina and Moreno, by examining the correlations between absorption rate constants experimentally found in the small intestine and in the colon of the rat, and two types of partition constants for a series of ring-substituted anilines, of low to medium molecular weight. Evidence is given which demonstrates the reliability of the bihyperbolic equation for the small intestine data, showing the importance of the type of substitution in the absorption rate of compounds; for the colonic data, the collapsed, monohyperbolic form of this equation (i.e., the Wagner-Sedman equilibrium model) applies, independent of the nature and position of the group substituents in the aniline molecule. This means that, as the bihyperbolic model equation predicts, aqueous pore diffusion is a crucial factor, as important as membrane permeation, in absorption in the small intestine, whereas in the colon only this latter route is operative. The perspectives opened by the application of the model to gastrointestinal absorption studies are also discussed.

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.

Intestinal absorption-partition relationships: A tentative functional nonlinear model

Models and equations designed to elucidate passive intestinal absorption mechanisms by analysis of the relationship between the absorption rate constant (ka)and either the partition coefficients (P)or a related partition constant for homologous series of substances, are reviewed. Classical nonlinear physical models, such as those which assume the existence of a nonstirred layer or equilibrium extraction, predict sigmoidal or hyperbolic relationships between ka and P,whereas other models, which regard the membrane as a heterogeneous multicompartment system, predict parabolic or bilinear relationships between log kaand log P.In the present paper, an alternative model is proposed, which incorporates the Wagner-Sedman equilibrium extraction model together with the existence of pores, which play a fundamental role for compounds below 250in molecular weight. Several apparently contradictory absorption-partition literature data are shown to be highly consistent with the tentative model proposed.

A novel approach to determining physicochemical and absorption properties of 6-fluoroquinolone derivatives: experimental assessment

The ToSS MoDe approach is used to estimate the n-octanol/buffer partition coefficient, the apparent intestinal absorption rate constant and intestinal permeability from a 6-fluoroquinolone data set. Improved in silico methods for predicting a drugs ability to be transported across biological membranes and other biopharmaceutical properties is highly desirable to optimize new drug development. The physicochemical property (Log P) of 26 6-fluoroquinolone derivatives and the absorption properties (Log K(a) and Log P(eff)) of 21 derivatives were well described by the present approach. The models obtained confirm the important role of lipophilicity in the absorption process and its relation with the piperazinyl ring spectral moment and general local spectral moment. The normalized group contributions to each property, at the R4 and R5 positions of a 6-fluoroquinolone framework, were calculated. Principal factor analysis between these contributions and the Hammett and Hansch constant, molar refractivity and sterimol parameters was also carried out. Three principal factors explained 78% of the total variance and the correlation coefficients were higher than 0.98. The isocontribution zone analysis for the Log P and Log K(a) of Sarafloxacin and Sparfloxacin, used as external corroboration compounds, was carried out. The absorption rate constants (in situ rat gut technique) for these drugs were also evaluated, and the results were compared with the values predicted by theoretical models for evaluating predictive performance. The present approach proved to be a good method for studying the oral absorption of drug candidates in drug development studies.

Non‐linear Intestinal Absorption Kinetics of Cefadroxil in the Rat

Abstract— Absorption of Cefadroxil in a selective intestinal absorption area (the proximal third of the small intestine) of the anaesthetized rat, at seven initial perfusion concentrations, ranging from 0·01 to 10·0 mg mL−1, is shown to be a non‐linear transport mechanism. With the aid of computer‐fitting procedures based on differential and integrated forms of Michaelis‐Menten equation, Vm and Km values of 36·7–37·3 mg h−1 and 12·0–13·0 mg, respectively, were found. The statistical parameters were better than those obtained both for first‐order and for combined Michaelis‐Menten and first‐order kinetics. There is no evidence for substantial passive diffusion processes. The results reported here, together with allometric considerations and literature data analysis, may help to explain some particular non‐linear features of plasma level curves associated with the administration of fairly high oral doses of Cefadroxil to humans.

Absorption-partition relationships for true homologous series of xenobiotics as a possible approach to study mechanisms of surfactants in absorption. II. Aromatic amines in rat small intestine

Abstract The previously proposed approaches in order to interpret the mechanisms elicited by the nonionic surfactant polysorbate 80 in the colonic absorption of 4-alkylanilines are extended here to the absorption of the same compounds in the rat small intestine, where compound behaviour seems to be complicated by the existence of a pore diffusion pathway, simultaneous with membrane absorption. Globally considered, the effects of surfactant in the intestinal absorption of anilines relative to the behaviour of these compounds in free solution are much less evident than in colon for low-molecular-weight hydrophilic compounds of the series, for which pore absorption is highly operative, but, as lipophilicity and molecular weight increase, the effects of surfactant become more and more significant, showing a close resemblance with those observed in colon. In the absence of surfactant, a bihyperbolic correlation can be established between intestinal absorption rate constants of anilines and partition constants. On this basis, the apparently complex absorption-partition correlations found in the presence of surfactant at the critical micelle concentration are explained here by assuming that pore absorption of the compounds is virtually unaffected by surfactant at this concentration, contrarily to that which occurs with membrane permeation, for which the same effects as found on bulk rate constants in colon are observed; a clearly linear and double-logarithmic correlation can be established between membrane absorption rate constants and partition constants, thus indicating that two main effects of the surfactant are elicited i.e. the removal of the limiting effect of the aqueous diffusion layer adjacent to the membrane, and an increased membrane polarity. At 5% surfactant concentration in the perfusion fluid, clearly supramicellar, correlations between membrane intestinal absorption rate constants and partition constants become, as occurred with bulk constants in colon, bilinear, due to the multiple-phase equilibrium arising from micellar solubilization of anilines; pore absorption constants are greatly reduced at this concentration, but correlate well with partition constants through an inverse hyperbolic equation as in the former cases. Biopharmaceutical implications of these observations are briefly discussed.

Influence of Permanent Cannulation of the Jugular Vein on Pharmacokinetics of Amoxycillin and Antipyrine in the Rat

The effect of chronic cannulation of the rat jugular vein on the pharmacokinetics of amoxycillin and antipyrine administered by the i.v. and oral routes has been evaluated. Animals that received the i.v. dose of amoxycillin on the eighth day after jugular vein cannulation showed decreased clearance (4.0 ± 0.3 ml/min) and steady-state volume of distribution (105 ± 8 ml) compared to animals that received the i.v. dose on the fourth day (5.5 ± 1.1 ml/min and 155 ± 17 ml, respectively). Rats first dosed by the i.v. route showed an oral bioavailability of 54 ± 12%, whereas for those first dosed by the oral route the calculated bioavailability was 31 ± 6%. Antipyrine was administered to rats by the i.v. and oral routes on the first and fourth days after jugular vein cannulation. Animals intravenously dosed on the fourth day showed a decreased clearance (1.9 ± 0.3 ml/min) compared to rats intravenously dosed on the 1st day (2.7 ± 0.6 ml/min). Antipyrine bioavailability was larger in animals first dosed by the i.v. route than in animals first dosed by the oral route (173 ± 43 and 74 ± 15%, respectively). These results argue against the use of crossover studies in rats with permanently implanted cannulas since kinetic changes induced by cannulation can be larger than previously proposed.

Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption I. Studies with polysorbate and taurocholate in rat colon

Some expected differences between synthetic and natural bile acid surfactants relative to their influences on xenobiotic absorption are briefly outlined on the basis of literature data. Then, experimental work is presented which shows that these differences exist and that they can be even more relevant than suspected. Absorption tests were developed in rat colon in situ with polysorbate (synthetic) and sodium taurocholate (natural) surfactants, using a homologous series of phenylalkylcarboxylic acids as test compounds. At the critical micelle concentration (CMC), the two previously reported actions of synthetic surfactants on xenobiotic absorption (i.e. the increase in absorbing membrane polarity, and the nullification of the resistance of the aqueous boundary layer adjacent to the membrane to solute penetration) were exerted ad libitum by polysorbate, while taurocholate completely lacked the latter action (it is even possible that the opposite exists i.e., an increase of the aqueous layer resistance to solute diffusion), although it apparently produces an increase in membrane polarity. At supramicellar concentrations (SMC), the solubilising action of taurocholate was almost negligible as compared with that of polysorbate. It is concluded that, as far as colonie absorption is concerned, polysorbate and taurocholate behave as different biophysical species, which could lead to substantially dissimilar in vivo effects.

Consistency of Carbopol 971-P NF gels and influence of soluble and cross-linked PVP.

A study is made of the polymerization process of polyacrylic acid, commercially known as Carbopol 971 NF, assessing its consistency as a function of the degree of neutralization at pH values from 3 to 12, approximately. Percentage concentrations ranging from 0.1 to 1.4% (w/w) were studied. The gels obtained were non-Newtonian, and pseudoplastic. As concentration and pH rise, the consistency of the gels increase to a maximum, which appears between pH 6 and 8, allowing their use as vehicles in bioadhesive formulations for mucosal application. Over the increasing viscosity interval, functions were obtained to indicate the consistency of the gel as a function of pH and concentration. Since the correlation between the theoretical and experimental results is excellent, the equation found can be used to theoretically calculate the working concentration and pH required to secure the necessary consistency for a given vehicle. The addition of soluble polyvinylpyrrolidone (PVP), and cross-linked PVP (PVPP) does not substantially modify the rheological behavior of the gels, thus permitting their addition to usual vehicles.