A preclinical study to model taurine pharmokinetics in the undernourished rat.

Malnutrition is a common feature of chronic and acute diseases, often associated with a poor prognosis, including worsening of clinical outcome, owing, among other factors, to dysfunction of the most internal organs and systems affecting the absorption, metabolism and elimination of drugs and nutrients. Taurine is involved in numerous biological processes and is required in increased amounts in response to pathological conditions. The aim of this study was to describe the behaviour of taurine in well-nourished (WN) rats and to analyse the influence of protein-energy undernutrition on the pharmacokinetic (PK) parameters of taurine, using a PK model. Wistar rats were randomly distributed into two groups, WN and undernourished (UN), and taurine was administered intravenously or orally at different doses: 1, 10 and 100 mg. Population pharmacokinetic modelling of plasma levels was performed using the NONMEM 7.2 program. Several distribution and absorption models were explored in combination with dose and/or time covariate effects. Covariates such as nutritional status, serum albumin, body weight and score of undernutrition were used. A two-compartment population pharmacokinetic model with zero-order endogenous formation, passive absorption, first-order kinetics distribution and non-linear elimination with parallel Michaelis-Menten excretion and reabsorption processes best described taurine pharmacokinetics. Undernutrition acted as a covariate reducing the V max of the active elimination process. Data analysis showed linear absorption and distribution, and non-linear elimination processes for taurine. Elimination of taurine was reduced in UN animals, suggesting that the reabsorption process via the secretion transporter was modified in that group.

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-fold) when this was encapsulated into cationic nanospheres and administered by passive diffusion than when the triclosan solution was employed. The amount of triclosan retained within the skin when the cationic nanospheres were administered by iontophoresis was 3.1-fold greater than when the triclosan solution was administered by passive diffusion. Iontophoresis proved to be effective in enhancing the passage of triclosan in solution throughout the skin, whereas the triclosan nanospheres could achieve a local effect by forming a controlled release dermal depot.

The Usefulness of In Vitro Percutaneous Absorption Experiments Applying the Infinite Dose Technique to Predict In Vivo Plasma Levels: Comparison of Model-Predicted and Observed Plasma Concentrations of Nortriptyline in Rats.

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

Composition influence on pulmonary delivery of rifampicin liposomes.

The effects of lipid concentration and composition on the physicochemical properties, aerosol performance and in vitro toxicity activity of several rifampicin-loaded liposomes were investigated. To this purpose, six liposome formulations containing different amounts of soy phosphatidylcholine and hydrogenated soy phosphatidylcholine, with and without cholesterol and oleic acid, were prepared and fully characterized. Uni- or oligo-lamellar, small (~100 nm), negatively charged (~60 mV) vesicles were obtained. Lipid composition affected aerosol delivery features of liposomal rifampicin; in particular, the highest phospholipid concentration led to a better packing of the vesicular bilayers with a consequent higher nebulization stability. The retention of drug in nebulized vesicles (NER%) was higher for oleic acid containing vesicles (55% ± 1.4%) than for the other samples (~47%). A549 cells were used to evaluate intracellular drug uptake and in vitro toxicity activity of rifampicin-loaded liposomes in comparison with the free drug. Cell toxicity was more evident when oleic acid containing liposomes were used.

Quantification of nortriptyline in plasma by HPLC and fluorescence detection.

A simple, sensitive and specific high-performance liquid chromatography method has been developed for the determination of nortriptyline (NT) in plasma samples. The assay involved derivatization with 9H-fluoren-9-ylmethyl chloroformate (Fmoc-Cl) and isocratic reversed-phase (C(18)) chromatography with fluorescence detection. The developed method required only 100 microl of plasma sample, deproteinized and derivatized in one step. Calibration curves were lineal over the concentration range of 5-5000 ng/ml. The derivatization reaction was performed at room temperature in 20 min and the obtained NT derivative was stable for at least 48 h at room temperature. The within-day and between-day relative standard deviation was below 8%. The limit of detection (LOD) was 2 ng/ml, and the lower limit of quantification (LLOQ) was established at 10 ng/ml. The method was applied on plasma collected from rats, at different time intervals, after intravenous administration of 0.5 mg of NT.