Bioactivity of Ceftazidime and Fluconazole Included in Polymethyl Methacrylate Bone Cement for Use in Arthroplasty.

BACKGROUND: The microorganisms that most frequently cause prosthetic joint infection are methicillin-resistant Staphylococcus aureus and gram-negative aerobic bacillus. Studies have documented the efficacy of mixing antibiotics with polymethyl methacrylate, but that of antifungal drugs has not received much attention. The objective of this in vitro study was to characterize the elution profile and bioactivity of ceftazidime and fluconazole when incorporated into bone cement in proportions intended for prophylaxis and treatment of bone infections. METHODS: Antibiotic-loaded bone cement cylinders in a proportion of 1:40 and 4:40 (ratio of grams of antibiotic to grams of cement) were assayed. Drug delivery was investigated in a flow-through dissolution apparatus (SotaxCE7). To assess bioactivity, antibiotic concentrations were simulated in the joint space of 1000 patients. Antibacterial properties were evaluated by counting colony forming units and the inhibition-halo test. RESULTS: The ratio of released ceftazidime and fluconazole was 453% and 648%, respectively, higher when used for treatment proportions than prophylaxis proportions. A bioactivity simulation exercise showed that the efficacy of ceftazidime/fluconazole determined as the amount of drug is released at the active site in the first 3 days after surgery would depend on the sensitivity of the microorganism and would increase substantially after drain removal. The microbiology study showed that biofilm formation by Pseudomonas aeruginosa could be a problem when ceftazidime was used in treatment or prophylaxis proportions. CONCLUSION: Our in vitro findings suggest that ceftazidime and fluconazole can be added into polymethyl methacrylate for the prevention/treatment of infections associated to joint surgery. Their efficacy depends on the sensitivity of the microorganism causing the infection.

Development of curcumin loaded sodium hyaluronate immobilized vesicles (hyalurosomes) and their potential on skin inflammation and wound restoring.

In the present work new highly biocompatible nanovesicles were developed using polyanion sodium hyaluronate to form polymer immobilized vesicles, so called hyalurosomes. Curcumin, at high concentration was loaded into hyalurosomes and physico-chemical properties and in vitro/in vivo performances of the formulations were compared to those of liposomes having the same lipid and drug content. Vesicles were prepared by direct addition of dispersion containing the polysaccharide sodium hyaluronate and the polyphenol curcumin to a commercial mixture of soy phospholipids, thus avoiding the use of organic solvents. An extensive study was carried out on the physico-chemical features and properties of curcumin-loaded hyalurosomes and liposomes. Cryogenic transmission electron microscopy and small-angle X-ray scattering showed that vesicles were spherical, uni- or oligolamellar and small in size (112-220 nm). The in vitro percutaneous curcumin delivery studies on intact skin showed an improved ability of hyalurosomes to favour a fast drug deposition in the whole skin. Hyalurosomes as well as liposomes were biocompatible, protected in vitro human keratinocytes from oxidative stress damages and promoted tissue remodelling through cellular proliferation and migration. Moreover, in vivo tests underlined a good effectiveness of curcumin-loaded hyalurosomes to counteract 12-O-tetradecanoilphorbol (TPA)-produced inflammation and injuries, diminishing oedema formation, myeloperoxydase activity and providing an extensive skin reepithelization. Thanks to the one-step and environmentally-friendly preparation method, component biocompatibility and safety, good in vitro and in vivo performances, the hyalurosomes appear as promising nanocarriers for cosmetic and pharmaceutical applications.

Impact of nutritional status on the pharmacokinetics of erlotinib in rats.

Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in the mild-undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. Copyright © 2015 John Wiley & Sons, Ltd.

Design, characterization and in vitro evaluation of 5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colon specific delivery.

The objective of this study was to prepare NS-chitosan microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. Microparticles can spread out over a large area of colon allowing a more effective local efficacy of 5-ASA. N-Succinyl-chitosan was chosen as carrier system because of its excellent pharmaceutical properties in colon drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive properties, and low toxicity. It was prepared by introducing succinic group into chitosan N-terminals of the glucosamine units. 5-ASA loaded NS-chitosan microparticles were prepared using spray-drying. As a control, a matrix obtained by freeze-drying technique was also prepared and tested. Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction studies show the 5-ASA/NS-chitosan electrostatic interactions in both the systems. Mean size of the microparticles was around 5 µm, zeta potential value of both systems was always negative. Scanning electron microscopy (SEM) images show an acceptable spherical non porous structure of microparticles. In vitro swelling and drug release studies were in accordance with the polymer properties, showing the highest swelling ratio and drug release at pH=7.4 (colonic pH) where microparticles were able to deliver more than 90% of 5-ASA during 24h experiments. Rheological studies are in accordance with the swelling and release studies.

Animal model of undernutrition for the evaluation of drug pharmacokinetics / Modelo de desnutrición animal para la evaluación de estudios de farmacocinética

Background: Protein energy malnutrition is a public health problem affecting a great number of people. Pathophysiological imbalances in malnourished individuals have a profound impact on drug pharmacokinetics. Objective: To develop an animal model of undernutrition using male Wistar rats to be used to assess, in further studies, the impact of nutritional status on the oral bioavailability and pharmacokinetics of drugs. Desing: Animals were randomly assigned to one of two groups and fed different diets for 26 days: WN (well-nourished/regular diet, N = 61) and UN (under-nourished/protein-calorie restricted diet, N = 72). Assessment of the animals' nutritional status was performed taking into account serum albumin, total cholesterol level and total body weight. A kinetic model incorporating population kinetic analysis (NONMEM) was developed to analyze body weight versus time profiles in the adaptation period following administration of the two aforementioned diets. Results: Serum albumin plasma levels were lower than 2.3 g/dL in 80% (60/72) of malnourished animals at the end of the adaptation period. The range of the total serum cholesterol was similar in both groups at the end of the adaptation period. Total body weight in all cases was less than 230 g for malnourished animals and higher than 240 g for well-nourished animals. The kinetic model assayed was confirmed to be an expansion module characterized by linear weight gain and a decline module characterized by exponential weight loss, where the weight loss rate constant is an exponential function of time. The bootstrap resampling method confirmed the stability of the model eventually selected. Conclusions: The animal model developed in this study is reliable and could be of use in evaluating the impact of nutritional state on the pharmacokinetics of drugs. The proposed mathematical model allows the body weight of animals to be predicted at a given time taking into account the diet followed in the experimental period (AU)

Antecedentes: La desnutrición calórico protéica es un problema de salud que afecta a un número de personas muy elevado. Las alteraciones fisiopatológicos originadas por la desnutrición tienen una repercusión elevada en el comportamiento farmacocinético de los fármacos. Objetivo: Desarrollar un modelo de desnutrición en ratas Wistar macho que pueda utilizarse para evaluar el impacto del estado nutricional sobre la biodisponibilidad oral y farmacocinética de los fármacos. Diseño: Los animales fueron asignados de forma aleatoria a uno de los dos grupos y alimentados con diferentes dietas durante 26 días: WN (dieta normo-nutrida/regular, N = 61) y UN (dieta restringida/calórico-proteica N = 72). La clasificación del estado nutricional de los animales se realizó teniendo en cuenta los niveles de albúmina sérica y colesterol total, y el peso corporal total. Se ha desarrollado un modelo cinético poblacional para analizar la evolución del peso corporal de los animales durante el periodo de adaptación. Resultados: Al final del periodo de adaptación los niveles de albúmina plasmática fueron inferiores a 2,3 g/dL en el 80% (60/72) de los animales desnutridos. Sin embargo, los valores de colesterol total en suero fueron similares en ambos grupos. El peso corporal total de los animales desnutridos fue inferior a 230 g y superior a 240 g para los animales alimentados en condiciones de normonutrición. El modelo de cinético de evolución del peso seleccionado se caracteriza por una cinética combinada lineal y exponencial. La fracción lineal representa el aumento de peso, y la fracción exponencial, que a su vez es función del tiempo, caracteriza la pérdida de peso del animal. La estabilidad del modelo seleccionado se ha realizado utilizando la técnica de remuestreo (bootstrap) y la validación mediante el test de predicción visual (visual predictive check, VPC). Conclusiones: El modelo animal desarrollado en este estudio puede ser de utilidad para evaluar el impacto del estado nutricional sobre la farmacocinética de los fármacos. El modelo matemático propuesto permite predecir el peso corporal de los animales, teniendo en cuenta la dieta la dieta administrada durante el período experimental (AU)

N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: in vivo study with TNBS-induced colitis model in rats.

5-Aminosalicylic acid (5-ASA) loaded N-Succinyl-chitosan (SucCH) microparticle and freeze-dried system were prepared as potential delivery systems to the colon. Physicochemical characterization and in vitro release and swelling studies were previously assessed and showed that the two formulations appeared to be good candidates to deliver the drug to the colon. In this work the effectiveness of these two systems in the treatment of inflammatory bowel disease was evaluated. In vitro mucoadhesive studies showed excellent mucoadhesive properties of both the systems to the inflamed colonic mucosa. Experimental colitis was induced by rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into male Wistar rats. Colon/body weight ratio, clinical activity score system, myeloperoxidase activity and histological evaluation were determined as inflammatory indices. The two formulations were compared with drug suspension and SucCH suspension. The results showed that the loading of 5-ASA into SucCH polymer markedly improved efficacy in the healing of induced colitis in rats.

A pharmacokinetic model for evaluating the impact of hepatic and intestinal first-pass loss of saquinavir in the rat.

The aim of this study was to quantify the intestinal and hepatic first-pass loss of saquinavir and to assess the effect of coadministration of ritonavir on this first-pass loss. Single doses of 12, 24, and 48 mg of saquinavir and a dose of 24 mg of saquinavir/6 mg of ritonavir were orally, intravenously, or intraperitoneally administered to 94 rats. Ten groups of animals were studied. A semiphysiological pharmacokinetic model incorporating a population pharmacokinetic analysis [nonlinear mixed-effects model (NONMEM)] was developed to analyze plasma concentration-time profiles after administration via each of the three above-mentioned routes. This model confirmed that saturable metabolism in hepatocytes and enterocytes and dose-dependent precipitation in the peritoneal cavity after intraperitoneal administration characterize the pharmacokinetics of SQV. It also demonstrated that low oral bioavailability of saquinavir is due mainly to intestinal rather than to hepatic first-pass metabolism. In addition, it was shown that ritonavir diminished saquinavir clearance through competitive inhibition. The present report presents a new pharmacokinetic model applied in rats to evaluate the impact of hepatic and intestinal first-pass loss on oral bioavailability.

Animal model of undernutrition for the evaluation of drug pharmacokinetics.

BACKGROUND: Protein energy malnutrition is a public health problem affecting a great number of people. Pathophysiological imbalances in malnourished individuals have a profound impact on drug pharmacokinetics. OBJECTIVE: To develop an animal model of undernutrition using male Wistar rats to be used to assess, in further studies, the impact of nutritional status on the oral bioavailability and pharmacokinetics of drugs. DESIGN: [corrected] Animals were randomly assigned to one of two groups and fed different diets for 26 days: WN (well-nourished/regular diet, N = 61) and UN (under-nourished/protein-calorie restricted diet, N = 72). Assessment of the animals' nutritional status was performed taking into account serum albumin, total cholesterol level and total body weight. A kinetic model incorporating population kinetic analysis (NONMEM) was developed to analyze body weight versus time profiles in the adaptation period following administration of the two aforementioned diets. RESULTS: Serum albumin plasma levels were lower than 2.3 g/dL in 80% (60/72) of malnourished animals at the end of the adaptation period. The range of the total serum cholesterol was similar in both groups at the end of the adaptation period. Total body weight in all cases was less than 230 g for malnourished animals and higher than 240 g for well-nourished animals. The kinetic model assayed was confirmed to be an expansion module characterized by linear weight gain and a decline module characterized by exponential weight loss, where the weight loss rate constant is an exponential function of time. The bootstrap resampling method confirmed the stability of the model eventually selected. CONCLUSIONS: The animal model developed in this study is reliable and could be of use in evaluating the impact of nutritional state on the pharmacokinetics of drugs. The proposed mathematical model allows the body weight of animals to be predicted at a given time taking into account the diet followed in the experimental period.

Bioavailability and pharmacokinetic model for ritonavir in the rat.

The aim of this study is to investigate in vivo the oral bioavailability of ritonavir and to evaluate the pharmacokinetic model that best describes the plasma concentration behavior after oral and intravenous administration. Male Wistar rats were intravenously administered at 3 mg dose of pure ritonavir and oral administered at 4.6 +/- 2.5 mg of diluted Norvir. Blood samples were taken by means of the jugular vein for a 24 h period of time. An analytical high-performance liquid chromatography (HPLC) technique was developed in order to quantify ritonavir plasma concentrations. A nonlinear modeling approach was used to estimate the pharmacokinetic parameters of interest. Results showed that a two-compartmental model with zero-order kinetic in the incorporation process of ritonavir into the body better fitted intravenous and oral data. The estimated oral bioavailability by means of noncompartmental and compartmental approaches resulted in 74% and 76.4%, respectively. These values confirm the ones obtained by other authors in the rat. In conclusion, a zero-order kinetic in the incorporation process at the administered doses suggests the saturation of the possible specialized transport mechanisms involved in the incorporation of ritonavir into the body. These results could justify the use of low doses of ritonavir when improving the bioavailability of other protease inhibitors (PIs) is required.

Labetalol absorption kinetics: rat small intestine and colon studies.

Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 microM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the intestine (1.42 +/- 0.05/h) and the colon (1.13 +/- 0.06/h), V(m) and K(m) of the input process (9.85 +/- 4.98 microM/h, and 10.44 +/- 26.16 microM, respectively) and K(m) of an efflux system (0.53 +/- 1.16 microM) and V(m) in both intestinal segments (2.60 +/- 11.37 microM . /h in the intestine and 0.66 +/- 1.38 microM . /h in the colon). The efflux carrier implicated is identified by means of several inhibition experiments, whose inhibition ability is mathematically estimated. Results suggest the p-glycoprotein as responsible for the efflux of labetalol.

Modelling intestinal absorption of salbutamol sulphate in rats.

The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium between salbutamol sulphate concentrations in lumen and enterocyte, and the salbutamol sulphate absorption was best described by a simultaneous passive diffusion (ka = 0.636 h(-1)) and active absorption (VMax = 0.726 mM/h, Km = 0.540 mM) processes from intestinal lumen to enterocyte, together with an active capacity-limited P-gp efflux (V'max = 0.678 mM/h, K'm = 0.357 mM) from enterocyte to intestinal lumen. The extent of salbutamol sulphate absorption in rat small intestine can be improved by NaN3, grapefruit juice and verapamil.

Influencia del propilenglicol sobre las propiedades bioadhesivas de un hidrogel de Carbopol 971-P / No disponible

Se ha estudiado el comportamiento bioadhesivode un gel de Carbopol 971-P, en presenciade diferentes concentraciones de propilenglicol(10%, 30%, 50%, 70%, m/m). A partir delas curvas fuerza-desplazamiento se han calculadola fuerza máxima y el trabajo de adhesión.El estudio comparativo de los valores mediosdel trabajo de adhesión indica que noexisten diferencias significativas (P<0,05) entreel hidrogel de Carbopol 971-P sin propilenglicol(control) y los hidrogeles adicionados depropilenglicol a las concentraciones más elevadas(10 y 30%, respectivamente). Se concluyeque, cuando se pretende utilizar Carbopol971-P en preparaciones adhesivas para la administraciónde fármacos de baja hidrosolubilidad,es posible incrementar la concentraciónde fármaco disuelto en el sistema bioadhesivo,mediante la incorporación de propilenglicol enconcentraciones de hasta un 30% (m/m), sinque se modifique significativamente su capacidadbioadhesiva

The influence of different concentrations ofpropylene glycol (10%, 30%, 50%, 70%, w/w)on the properties of bioadhesion of Carbopol971-P gels has been analyzed. From force-deformationcurves, the peak force and the tensilework have been calculated. The comparativestudy of the mean values of tensile work indicatethat no significant differences (P<0.05) existamong the Carbopol 971-P hydrogels withoutpropylene glycol (control) and with propyleneglycol for the lowest concentrations (10 and30%, respectively). Therefore, it seems possibleto use Carbopol 971-P hydrogels addedwith propylene glycol until a concentration of30% (w/w), in order to increase drug solubility,without significant modification of its capacityof bioadhesion

Use of nonlinear mixed effect modeling for the intestinal absorption data: application to ritonavir in the rat.

The aim of this study is to investigate in situ the mechanisms involved in the gastrointestinal absorption of ritonavir in the rat, as an animal model for preclinical studies of anti-HIV agents in vivo. Four ritonavir solutions (40, 27, 13 and 7 microM) in the presence of 1% dimethylsulfoxide (DMSO) were perfused in the small intestine of anaesthetised rats. Effects of DMSO on the intestinal permeability were investigated using solutions containing antipyrine 1.33 mM and ritonavir 7 microM with and without 1% of DMSO. Antipyrine and ritonavir transport was not modified in the presence of 1% of DMSO. The population pharmacokinetic parameters of the ritonavir intestinal transport were obtained by means of nonlinear mixed effect modelling approach according to a nonlinear absorption and nonlinear secretion. The absorption and secretion kinetic parameters for ritonavir were: Vm=47.6 microM/h; Km=8.77 microM; Vms=3.66 microM/h and Kms=0 microM. The interindividual variability found to ritonavir Vm 13.1%, and the residual variability was 8.98%. The Kms value support the saturation of the carrier at the range of concentrations of ritonavir assayed. The interindividual variability value of the Vm could explain, at least in part, the variability in absorption rate constants observed.

Importancia de los sistemas lipídicos nonoparticulares (SLN) en preparados dermatológicos / Importance of the lipidics nonoparticulars systems in dermatological preparations

Los sistemas lipídicos nanoparticulares (SLN) representan una excelente alternativa a los diferentes sistemas transportadores de ingredientes activos de tamaño coloidal: microemulsiones, liposomas y micro- y nanopartículas poliméricas. Los SLN se han utilizado tanto en el campo farmacéutico como en el cosmético. Las ventajas que proporcionan cuando se utilizan para la administración tópica de principios activos, son evidentes: protección de compuestos lábiles frente a la degradación química, control de la liberación de ingredientes activos, desarrollo de un efecto oclusivo y un efecto barrera frente a las radiaciones ultravioleta. No obstante, presentan algunos incovenientes como su capacidad de carga limitada y la posible liberación súbita "efecto burst" del principio activo durante el período de almacenamiento. En esta revisión se analiza la composición, el método de elaboración por homogeneización de presión elevada, los mecanismos implicados en la liberación y las aplicaciones de estos sistemas en el campo de los preparados dermatológicos (AU)

Pharmacokinetic models for the saturable absorption of cefuroxime axetil and saturable elimination of cefuroxime.

Since oligopeptidic drugs such as beta-lactam antibiotics share the same carriers in humans and animals, the absorption and elimination kinetics of cefuroxime (C) were investigated in rats. Plasma C concentrations were measured by liquid chromatography. Pharmacokinetics and bioavailability of C in the rat were examined after intravenous (i.v.) administration at three doses (1.78, 8.9 and 17.8mg) of cefuroxime sodium and oral administration at two doses (2.02 and 8.9mg) of cefuroxime axetil (CA). Preliminary fits using data from intravenous administration of C showed that the drug disposition kinetics were clearly nonlinear, with an increase in plasma clearance as the intravenous dose increased. After oral administration of CA, normalized C(max) was higher for smaller dose than for the largest dose. The population pharmacokinetic parameters were obtained by means of nonlinear mixed effect modelling approach according to a nonlinear elimination and nonlinear absorption two-compartment model. The nonlinear elimination could be attributed to a saturable renal tubular reabsorption of the antibiotic and nonlinear intestinal absorption of CA mediated by carrier system. The oral bioavailability of C, calculated by numeric integration of an amount of CA drug absorbed was 22 and 17% for 2.02 and 8.9mg of prodrug administered orally.

Intestinal transport of cefuroxime axetil in rats: absorption and hydrolysis processes.

Studies were performed using three cefuroxime axetil solutions (11.8, 118 and 200 microM) in three selected intestinal segments and one cefuroxime axetil solution (118 microM) in colon of anaesthetized rats. First-order absorption rate pseudoconstants, k(ap) and effective permeability coefficients, P(eff), were calculated in each set. Absorption of cefuroxime axetil can apparently be described as a carrier-mediated transport, which obeys Michaelis-Menten and first order kinetics in the proximal segment of the small intestine and a passive diffusion mechanism in the mean and distal segments. The absorption kinetic parameters for cefuroxime axetil were obtained: Vm=0.613 (0.440) microM min-1; Km=31.49(28.31) microM and ka=0.011(0.003) min-1. Parameters characterizing degradation of the prodrug were obtained in each intestinal segment: proximal segment k(dp)=0.0049(0.0003) min-1, mean segment, k(dm)=0.0131(0.0007) min-1 and distal segment k(dd)=0.019(0.0009) min-1. Therefore, in situ intestinal absorption of cefuroxime axetil in the proximal segment of the rat in the presence of variable concentrations of cefadroxil has been investigated in order to examine the inhibitory effect of cefadroxil on cefuroxime axetil transport. The data suggest that cefadroxil and cefuroxime axetil share the same intestinal carrier.

The influence of active secretion processes on intestinal absorption of salbutamol in the rat.

Salbutamol was perfused in the small intestine of rat using a standard rat gut "in situ" preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0mM); (2) at a 0.29mM concentration - thought to be close to the allometric dose in man - in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0mM); and (3) at 0.29mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0mM). In free solution, the mixed-order rate constants, k'(a), of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation of enzymatic systems responsible for the secretion of the drug from the enterocyte to the luminal fluid, a process that could explain the poor absorption of salbutamol. In the presence of sodium azide, the k(a) values increased about 1.5-fold, whereas in the presence of verapamil they increased two- to three-fold. These results indicate that salbutamol can act as a substrate of an intestinal secretory transport, which probably includes--at least in part--the enzyme P-glycoprotein, since verapamil has been shown to inhibit this enzyme by dose-dependent competition. This leads to a secretion-limited peroral absorption of salbutamol, which contributes to the poor oral bioavailability of the drug. The possible options for improving salbutamol absorption are discussed.

Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat.

The objectives of this study were to determine the oral bioavailability of cefuroxime (C) and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following single intravenous (IV), intraperitoneal (IP) and oral single doses. The same dose of C was administered by IV, IP and oral routes to three separate groups of rats (2.02 mg of cefuroxime axetil (CA) by the oral route or 1.78 mg of cefuroxime sodium (CNa) by IV and IP route). A two-compartment open model without lag time can predict the C disposition kinetics. The influence of the administration route on the pharmacokinetic parameters and AUC values was investigated by means of a one-way analysis of variance test. The results indicated that the first-pass effect in the intestine and liver reduce oral bioavailability when the drug is administered orally. Cefuroxime bioavailability after oral and IP administration estimated from the plasma levels was nearly 24 and 75%, respectively.

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 solution were obtained: maximum rate of absorption (Vmax) = 289.08 +/- 46.26 microM h-1, and Km = 162.77 +/- 31.17 microM. Cefuroxime axetil transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. On the other hand, the prodrug was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane before absorption occurred. This process reduces the prodrug fraction directly available for absorption. From a bioavailability point of view, therefore, the effects mentioned above can explain the variable and poor bioavailability following oral administration of cefuroxime axetil. Thus, future strategies in oral cefuroxime axetil absorption should focus on increasing the stability of the prodrug in the intestine by modifying the prodrug structure and/or targeting the compound to the absorption site.

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 solutions containing 0.5 mM baclofen with starting taurine concentrations ranging from 0 to 100 mM were perfused in rat jejunum, and the remaining concentrations of both compounds were measured. The apparent rate pseudoconstant of the drug clearly decreased as the remaining taurine concentration increased. The interaction can be described as a complete competitive inhibition plus a second component, K, noninhibited, K = 0.58 (+/- 0.03) h-1, Ki = 20.62 (+/- 4.04) mM, Vmi = 28.12 (+/- 6.12) mM h-1, Kmi = 11.71 (+/- 2.53) mM, Kai = 0.47 (+/- 0.10) h-1. A residual absorption of baclofen in the presence of high taurine concentrations was observed, which should be attributed to another transport system not associated with the taurine carrier. In order to elucidate whether or not taurine and beta-alanine carriers are two separate entities that baclofen can use for absorption, further experiments using beta-alanine and taurine together as inhibitors (baclofen, 0.5 mM; beta-alanine, 50 mM, and taurine, 50 mM) were developed. Results indicated that baclofen and both amino acids share the same carrier in the intestinal absorption process. We have completed studies using leucine, taurine, and GABA together as inhibitors of drug absorption. An isotonic perfusion solution of 0.5 mM baclofen in the presence of 50 mM leucine, 25 mM taurine, and 25 mM GABA was perfused. Under these conditions the absorption rate pseudoconstant of baclofen decreases until 0.080 h-1 (+/- 0.069). Practical implications of these phenomena are briefly discussed.