Polymeric nanospheres as strategy to increase the amount of triclosan retained in the skin: passive diffusion vs. iontophoresis

The aim of this study was to evaluate the passive and iontophoretic permeation of triclosan in human skin using a triclosan solution and triclosan-loaded cationic nanospheres in order to determine which of the two strategies is more effective in allowing the deposition of triclosan within the skin. Triclosan-loaded nanospheres were prepared by the emulsification-solvent displacement technique using aminoalkyl methacrylate (Eudragit® RL 100) as polymer matrix. Nanospheres of 261.0 ± 15.1 nm with a positive surface charge (Ψz = 26.0 ± 3.2 mV) were obtained. Drug loading was 62.0 ± 1.7%. Results demonstrated that the amount of triclosan retained within the skin was significantly greater (8.5-f…

Influence of gamma-aminobutyric acid on baclofen intestinal absorption.

Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by beta-alanine and therefore mediated, at least in part, by the beta-aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a gamma-aminoacid model compound, gamma-aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease a…

Partially competitive inhibition of intestinal baclofen absorption by beta-alanine, a nonessential dietary aminoacid.

In situ intestinal absorption of baclofen in the rat in the presence of beta-alanine has been investigated. Through the perfusion of 0.50 mM baclofen solutions containing variable concentrations of the aminoacid (from 5 to 100 mM), a partially competitive inhibition of baclofen absorption was characterized: absorption rate pseudoconstants of the spasmolytic drug decrease as beta-alanine concentration increases, until a limiting value is obtained (36.8 per cent of that found for baclofen alone). A computer method was developed in order to calculate parameters governing baclofen absorption in the presence of beta-aminoacid, with the following results: Vm = 11.22 mM h-1; Km = 7.42 mM; Ki = 2.4…

A rapid HPLC assay for zearalenone in laboratory cultures ofFusarium graminearum

A high pressure liquid chromatographic (HPLC) method to determine zearalenone in corn contaminated withFusarium graminearum is described. After extraction with methanol-water and solvent partition, samples were cleaned up by applying the extract to a disposable silica cartridge and by eluting the toxin with a mixture of hexane/dry ethyl ether (5/5). Separation was achieved by a reverse phase μBondapak C18 column followed by fluorescence detection using an excitation wavelength at 274 nm and an emission wavelength at 440 nm. Detection limit was about 5 ng. Recoveries ranging from 85.37 to 100.97%, in standard solutions range 30–0.5 µg/ml, were found.

P2-283: Dose individualization of Carboplatin in elderly patients with advanced non small cell lung cancer (ANSCLC): an exploratory analysis

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 w…

Intestinal absorption pathway of gamma-aminobutyric acid in rat small intestine.

Intestinal absorption of gamma-aminobutyric acid (GABA), as a model compound for gamma-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of beta-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They s…

Nonlinear intestinal absorption kinetics of cefuroxime axetil in rats.

Cefuroxime is commercially available for parenteral administration as a sodium salt and for oral administration as cefuroxime axetil, the 1-(acetoxy)ethyl ester of the drug. Cefuroxime axetil is a prodrug of cefuroxime and has little, if any, antibacterial activity until hydrolyzed in vivo to cefuroxime. In this study, the absorption of cefuroxime axetil in the small intestines of anesthetized rats was investigated in situ, by perfusion at four concentrations (11.8, 5, 118 and 200 microM). Oral absorption of cefuroxime axetil can apparently be described as a specialized transport mechanism which obeys Michaelis-Menten kinetics. Parameters characterizing absorption of prodrug in free solutio…

Evidence of a specialized transport mechanism for the intestinal absorption of baclofen

Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis-Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis-Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12.0 mg h-1 and 8.0 mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but …

Alternative Methods to Animal Testing in Safety Evaluation of Cosmetic Products

Abstract This chapter reviews alternative methods recommended for animal testing in various toxicological areas. An alternative model to achieve complete animal replacement for acute toxicity testing is not possible. Skin corrosion/irritation alternative methods have been validated and accepted. For eye irritation testing, no single method is able to replace the Draize rabbit eye test. Skin sensitization methods imply refinement and reduction of numbers of animals. An in vitro dermal absorption test could be an alternative to in vivo testing. There are no generally accepted alternative methods to replace the usual repeated-dose toxicity in vivo assays. To determine the genotoxic and mutagen…

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…

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 a…

Interaction of Taurine on Baclofen Intestinal Absorption: A Nonlinear Mathematical Treatment using Differential Equations to Describe Kinetic Inhibition Models

Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrations of inhibitor were also measured and incorporated into the model. Previously, kinetic absorption in situ parameters for taurine in free solution were obtained: Vm = 27.73 +/- 9.99 mM h-1, K(m) = 8.06 +/- 2.82 mM, Ka (passive difussion component) = 0.40 +/- 0.28 h-1. Isotonic …

Influence of leucine on intestinal baclofen absorption as a model compound of neutral α-aminoacids

The inhibitory effect of the essential alpha-aminoacid L-leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5-100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations however did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (+/- 0.08)h…

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 thr…