The pharmacokinetic study of Tanreqing and the interaction with cefixime in rat model of pneumonia by validated UPLC-MS/MS.

Combining traditional Chinese medicine and chemical drugs with antimicrobial activities has become more popular, but there is insufficient relevant research on such combinations. The Tanreqing injection (TRQI), a Chinese compound medicine, exhibits therapeutic effects in treating upper respiratory tract infections, severe influenza, and pneumonia. This research investigates the pharmacokinetics of TRQI in pneumonia model rats and explores the effect of the antibiotic cefixime on its metabolism. The pneumonia model rats were randomly divided into six groups: low, medium, and high (3, 6, and 12 mL kg-1) dose TRQI group, and a medium dose TRQI combined with cefixime (14.4 mg kg-1) group, with the remainder two groups were control group. Blood samples were collected from the tail vein at different time points between 0 and 24 h after injection. A sensitive and quick method based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established for the simultaneous determination of the 13 TRQI components in the blood samples. The analytes were separated on an XBridge™C18 column (2.1 mm × 150 mm, 5 µm), with the flow phase consisting of methanol and 0.1% formic acid water at a flow rate of 0.3 mL/min. The assay method met the biological sample determination requirements, demonstrating good adaptability and practicability for application in the pharmacokinetic study of TRQI in pneumonia model rats. Moreover, the method was used successfully in the interaction study of TRQI with cefixime. The results indicated that co-administration results in a significant change in the pharmacokinetic parameters of the main TRQI components. However, the changes in the pharmacokinetic characteristics of multiple TRQI components were inconsistent. Thus, the results of this drug combination under different pathological conditions in clinical applications were unpredictable. Therefore, more attention should be paid to the combined use of cefixime and TRQI in clinical applications to avoid the risk of adverse drug reactions in future studies.

Design and development of lipid modified chitosan containing muco-adhesive self-emulsifying drug delivery systems for cefixime oral delivery.

Current study was aimed to design and develop muco-adhesive self-nano emulsifying drug delivery system (SNEDDs) for improved pharmacokinetics of Cefixime (CFX) in rabbits. The components of SNEDDs formulation i.e., cinnamon oil, Tween® 80, and PEG 200 as oil, surfactant, and co-surfactant respectively were selected based on their high solubilizing capability of the drug. SNEDDs formulation was optimized using Design of experiments (D-optimal design) in terms of droplet size, poly dispersity index and zeta potential. The optimized SNEDDs formulation was studied for various parameters like droplet size, morphology, zeta potential, emulsification, optical clarity, thermodynamic stability, GIT stability, and robustness to dilution. CFX was loaded to optimized formulation to form CFX-SNEDDs. Furthermore, acyl-chitosan, a muco-adhesive agent, was added to CFX-SNEDDS to prepare CHT-CFX-SNEDDS. In vitro drug release showed the controlled release behavior reached a maximum value of 70 % at pH 6.8 within 24 h. The droplet size, atomic force microscopy, and optical clarity analysis revealed the formation of nanosized emulsion (156 ± 25 nm) with spherical morphology. Also in vivo pharmacokinetic studies on rabbits showed an increased drug plasma concentration for CHT-CFX-SNEDDs (15 ± 3 µg/mL) and CFX-SNEDDs (9 ± 2 µg/mL) in comparison with control CFX (4 ± 1 µg/mL). The results indicated that the developed CHT-CFX-SNEDDs with an increased degree of solubilization, permeation, and nanosized range emulsion enhance the oral performance of CFX.

Are oral cefuroxime axetil, cefixime and cefditoren pivoxil adequate to treat uncomplicated acute pyelonephritis after switching from intravenous therapy? A pharmacokinetic/pharmacodynamic perspective / Cefuroxima axetilo, cefixima y cefditoren pivoxil, ¿son adecuadas en la terapia secuencial de la pielonefritis aguda no complicada? Perspectiva farmacocinética y farmacodinámica

OBJECTIVES: The goal of this study is to assess, by means of pharmacokinetic/pharmacodynamic (PK/PD) analysis using the Monte Carlo simulation, the adequacy of oral cephalosporins cefuroxime axetil, cefixime and cefditoren at different dosing regimens as switch therapy after intravenous cephalosporin treatment in uncomplicated acute pyelonephritis. METHODS: The methodology included: (I) dosing regimen selection and acquisition of pharmacokinetic data; (II) microbiological data acquisition; and (III) Monte Carlo simulation to estimate the PTA (probability of PK/PD target attainment) and CFR (cumulative fraction of response), as indicators of treatment success. RESULTS: At the current susceptibility breakpoints defined by EUCAST and CLSI for either cefuroxime axetil or cefixime, the probability of bactericidal target attainment is zero for the dosage regimens simulated. Considering the bactericidal target %fT > MIC > 70%, the likelihood of the cefuroxime 500- mg q8 h regimen or the cefixime 200- mg q12h regimen producing this exposure or achieving this target is only above 90% for organisms yielding MICs ≤ 0.5 mg/l and MICs ≤ 0.25 mg/l, respectively. Cefditoren pivoxil 400 mg q12h provided probabilities of bactericidal target attainment of 80% or higher for MICs ≤ 0.03 mg/l, and ≤ 0.25 mg/l if considering total instead of free drug concentrations. CONCLUSIONS: The results of the PK/PD target attainment analysis reveal that the likelihood of treatment success based upon the current breakpoints proposed by either EUCAST or CLSI is low. Of the three cephalosporins, cefixime 400 mg q12 h prove to be the best option in oral APN treatment, although this regimen is currently off label

OBJETIVOS: El objetivo de este estudio es evaluar, mediante el análisis farmacocinético/farmacodinámico (PK/PD) empleando la simulación de Montecarlo, la idoneidad de las cefalosporinas orales cefuroxima axetilo, cefixima y cefditoren en diferentes regímenes de dosificación, como terapia secuencial tras el tratamiento intravenoso con cefalosporinas, en pielonefritis aguda no complicada. MÉTODOS: La metodología incluyó: 1) selección del régimen de dosificación y adquisición de datos farmacocinéticos; 2) adquisición de datos microbiológicos; y 3) simulación de Montecarlo para estimar la probabilidad de alcanzar el objetivo (PTA) PK/PD y la fracción de respuesta acumulada (CFR), como indicadores del éxito del tratamiento. RESULTADOS: Para los puntos de corte de sensibilidad actuales definidos por EUCAST y CLSI para cefuroxima axetilo o cefixima, la probabilidad de alcanzar el objetivo bactericida es cero para los regímenes de dosificación simulados. Teniendo en cuenta el objetivo bactericida %fT > MIC > 70%, la probabilidad de que el régimen de cefuroxima 500 mg/cada 8h o el régimen de cefixima 200 mg/cada 12 h produzca esta exposición o alcance este objetivo es solo superior al 90% para los organismos que producen MIC ≤ 0,5 mg/l y MIC ≤ 0,25 mg/l, respectivamente. Cefditoren pivoxil 400 mg/cada 12 h proporcionó probabilidades de alcanzar el objetivo bactericida del 80% o más para MIC ≤ 0,03 mg/l, y ≤ 0,25 mg/l si se considera el fármaco total en lugar de libre. CONCLUSIONES: Los resultados del análisis PK/PD revelan que la probabilidad de éxito del tratamiento basado en los puntos de corte actuales propuestos por EUCAST o CLSI es baja. De las 3 cefalosporinas, la cefixima 400mg/cada 12h resultó ser la mejor opción en el tratamiento oral de pielonefritis aguda, aunque este régimen está actualmente fuera de ficha técnica

Disposition kinetics, renal clearance and urinary excretion of cefixime in adolescent Pakistani boys - DRUG ANALYSIS REPORT.

OBJECTIVE: To investigate the role of environmental variation, genetic differences and age on disposition kinetics, renal clearance and urinary excretion of oral cefixime 400mg in healthy boys. METHODS: The cross-sectional study was conducted at the University of Agriculture, Faisalabad, Pakistan, from August 2014 to July 2015, and comprised healthy boys aged 12-17 years after oral administration of cefixime capsule 400mg. Serum and urine samples were collected before and after drug administration and were stored at - 20oC until evaluation of cefixime concentration in each sample by high performance liquid chromatography. Drug concentration versus time data was used for pharmacokinetic calculations using one compartment model. Data obtained for urinary excretion and renal clearance of cefixime was analysed using regression-correlation analysis. RESULTS: There were eight boys in the study. Mean values for elimination half-life, volume of distribution and total body clearance were 2.4}0.2 hours, 0.9}0.0L/kg and 0.3}0.0L/h/kg, respectively. The ratio of renal clearance of cefixime (0.7 ml/min/kg) to that of endogenous creatinine (0.8ml/min/kg) was 0.9. Cumulative mean percentage of cefixime excreted from young adolescent boys was 11.6 } 0.5%. CONCLUSION: Other than filtration, back-diffusion was also involved in renal handling of cefixime. There was enough indication that major portion of cefixime was excreted from a young body through bile.

A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx.

BACKGROUND: There are no fully oral recommended treatment regimens for gonorrhea. Inadequately treated pharyngeal gonococcal infections are a likely reservoir for transmission and development of antimicrobial resistance. We sought to determine an oral cefixime dosing regimen that would theoretically treat pharyngeal infections by gonococci with minimum inhibitory concentrations 0.5 µg/mL. METHODS: We conducted an open-label, nonrandomized, phase I pharmacokinetic and safety study of cefixime in 25 healthy male and female volunteers divided into 4 dosing cohorts (cohort A, 400 mg; cohort B, 800 mg; cohort C, 1200 mg; and cohort D, 800 mg every 8 hours × 3 doses [total dose 2400 mg]) with a target serum concentration of at least 2.0 µg/mL for more than 20 hours. Cefixime concentrations from serum and pharyngeal fluid were determined with use of a validated liquid chromatography-tandem mass spectrometry assay. Safety measures included laboratories, physical examinations, and symptom diaries. RESULTS: None of the single-dose regimens attained the target concentration; however, 50% of subjects in cohort D attained the target concentration. Variation in absorption and protein binding contributed to differences in concentrations. Pharyngeal fluid concentrations were negligible. The single-dose regimens were well tolerated; the multidose regimen resulted in mild to moderate gastrointestinal symptoms in 43% of subjects. CONCLUSIONS: None of the dosing regimens achieved the target concentration. However, the proposed theoretical target was extrapolated from penicillin data; there are no empirically derived pharmacokinetic/pharmacodynamic criteria for pharyngeal gonorrhea. Under alternative cephalosporin-specific therapeutic goals, the multidose regimen may be effective, although the absence of cefixime in pharyngeal fluid is concerning. A clinical trial evaluating efficacy and defining pharmacokinetic/pharmacodynamic outcomes may be warranted.

Employment of modified Fe3 O4 nanoparticles using thermo-sensitive polymer for extraction and pre-concentration of cefexime in biological samples.

Cefexime is a useful antibiotic that can be prescribed to treat bacterial infections. Nanoparticles have been widely marketed as a universal solution among scientists. Many studies have been performed to modify nanoparticles to make them functional as extraction and pre-concentration agents and drug carriers. Temperature-sensitive polymers belong to a group of substances that undergo a major change in their physical features in response to temperature. Recently developed polymers can be used in many different areas, including modification of nanoparticles. In order to modify this nanoparticle, grafting copolymerization of Fe3 O4 nanoparticles was performed using poly (N-vinylcaprolactam) and 3-allyloxy-1,2-propanediol. The optimum conditions for pre-concentration of cefexime were studied. Under these optimum conditions, extraction recovery of biological samples in the range of 71-89% was obtained. The limit of detection and precision of proposed method were 4.5 × 10-4 µg mL-1 and <4.11% (relative standard deviation), respectively. Based on the results from analysis of cefexime, in biological samples using the proposed method, the ability of this method to extract and pre-concentrate cefexime was confirmed. Also, satisfactory results from an in vitro study on drug release in simulated intestine media were obtained.

Double-tailed acyl glycoside niosomal nanocarrier for enhanced oral bioavailability of Cefixime.

Novel, safe, efficient, and cost effective surfactants from renewable resources has attracted attention for enhancing solubility and bioavailability of hydrophobic dugs. We report the synthesis, characterization, and biocompatibility of a novel non-ionic acyl glycoside double-tailed surfactant for niosomal drug delivery system. Structure of the surfactant was confirmed by 1H NMR and mass spectroscopy. Applications of surfactant in niosomal drug delivery were explored using Cefixime as model. The shape, size, and polydispersity index (PDI) of drug loaded vesicles were investigated with atomic force microscope (AFM) and dynamic light scattering (DLS). Drug entrapping efficiency (EE%) was determined using HPLC. Biocompatibility of the surfactant was evaluated by in vitro cytotoxicity, blood hemolysis, and in vivo acute toxicity. Bioavailability of the surfactant based formulation was investigated in rabbits using HPLC. Vesicles were found to be 159.76 ± 6.54 nm with narrow size distribution and spherical shape. EE% was found to be 71.39 ± 3.52%. Novel surfactant was non-cytotoxicity and hemo-compatible even at 1000 µg/mL concentration and was safe up to 2000 mg/kg body weight. The in vivo bioavailability of niosomal formulation showed elevated plasma concentration and decreased clearance of Cefixime. Current findings reveal that this novel surfactant is biocompatible and could be employed for niosomal drug delivery.

Time-kill curve analysis and pharmacodynamic modelling for in vitro evaluation of antimicrobials against Neisseria gonorrhoeae.

BACKGROUND: Gonorrhoea is a sexually transmitted infection caused by the Gram-negative bacterium Neisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic models describing the relationship between the concentration of antimicrobials and the minimum growth rate of the bacteria provide more detailed information than the MIC only. RESULTS: In this study, a novel standardised in vitro time-kill curve assay was developed. The assay was validated using five World Health Organization N. gonorrhoeae reference strains and a range of ciprofloxacin concentrations below and above the MIC. Then the activity of nine antimicrobials with different target mechanisms was examined against a highly antimicrobial susceptible clinical strain isolated in 1964. The experimental time-kill curves were analysed and quantified with a previously established pharmacodynamic model. First, the bacterial growth rates at each antimicrobial concentration were estimated with linear regression. Second, we fitted the model to the growth rates, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. A gradual decrease of bactericidal effects from ciprofloxacin to spectinomycin and gentamicin was found. The beta-lactams ceftriaxone, cefixime and benzylpenicillin showed bactericidal and time-dependent properties. Chloramphenicol and tetracycline were purely bacteriostatic as they fully inhibited the growth but did not kill the bacteria. We also tested ciprofloxacin resistant strains and found higher pharmacodynamic MICs (zMIC) in the resistant strains and attenuated bactericidal effects at concentrations above the zMIC. CONCLUSIONS: N. gonorrhoeae time-kill curve experiments analysed with a pharmacodynamic model have potential for in vitro evaluation of new and existing antimicrobials. The pharmacodynamic parameters based on a wide range of concentrations below and above the MIC provide information that could support improving future dosing strategies to treat gonorrhoea.

Development and evaluation of bilayer tablets of combination of antibiotics for the treatment of sexually transmitted disease

ABSTRACT The present research work was envisaged to develop bilayer tablets to improve therapeutic efficacy of antibiotic combination for the treatment of sexually transmitted diseases. The combination of two antibiotics i.e. cefixime trihydrate and ofloxacin were used for the preparation of bilayer tablets which act against genito-urinary infections. The formulations comprise of cefixime trihydrate as immediate release layer formulated using different superdisintegrants and ofloxacin as extended release layer containing HPMC K100M. Evaluation of bilayer tablets were performed for the immediate release cefixime layer and sustain release ofloxacin layer with optimization of excipients. The immediate release layer of cefixime showed complete release within 30 min and ofloxacin release was extended up to 24 hours. The similarity factor value of ofloxacin sustained release layer was found to be 87.01 for initial and 80.35 after 3 months stability when compared with marketed reference product. The present study revealed that cefixime trihydrate and ofloxacin bilayer tablets were successfully developed for the use against sexually transmitted infections.

Glycoside-based niosomal nanocarrier for enhanced in-vivo performance of Cefixime.

This study aimed to evaluate the potential of a novel glycoside non-ionic surfactant synthesized and characterized in our laboratory for increased oral bioavailability of Cefixime. The surfactant was synthesized by simple etherification of bergenin with bromoundecane and characterized by (1)H NMR and mass spectroscopy (MS). Biocompatibility of the surfactant (BRM-BG) was assessed by in-vitro cytotoxicity against NIH/3T3 cells and human blood hemolysis. In-vivo acute toxicity was evaluated in mices. Cefixime loaded BRM-BG niosomes were investigated for drug entrapment efficiency using HPLC and surface morphology and vesicle size by atomic force microscopy (AFM) and dynamic light scattering (DLS). The in-vivo oral bioavailability and pharmacokinetics studies were carried out using rabbits. Cefixime loaded BRM-BG vesicles were spherical in the size range of 178.66±8.17nm with a polydipersity index (PDI) of 0.20±0.01, offering an entrapment efficiency as high as 78.4±0.83%. When the surfactant was applied on NIH 3T3 tissue culture, as high as 90.77±3.15% and 86.86±3.02%, cell viability at 1000µg/mL concentration after 24 and 48h respectively were observed. The surfactant also caused 5.49±1.62% haemolysis and was found to be safe at a dose up to 2000mg/kg. In-vivo drug plasma concentration (Cmax) was found to be 9.69±1.22µg/mL, much higher than that resulting from the intake of commercial suspension and capsules. BRM-BG demonstrated to be safe and effective as carrier of Cefixime following oral dosing in rabbits. The BRM-BG surfactant delivery nano-system is relatively safe and in animal models it is an appropriate carrier for Cefixime, offering enhanced bioavailability compared to commercially available formulations of the drug.

PEPT1- and OAT1/3-mediated drug-drug interactions between bestatin and cefixime in vivo and in vitro in rats, and in vitro in human.

The purpose of the present study was to elucidate the transporter-mediated pharmacokinetics mechanism of drug-drug interactions (DDIs) between bestatin and cefixime. The plasma concentrations and bioavailabilities of bestatin and cefixime were decreased after oral co-administration in rats. The uptake in rat everted intestinal sacs of bestatin and cefixime were dramatically declined after co-administration of the two drugs. Bestatin and cefixime can mutually competitively inhibit the uptake by hPEPT1-HeLa cells. The plasma concentrations of bestatin and cefixime were increased; however, the cumulative biliary excretion had no significant change, and the cumulative urinary excretion and renal clearance of the two drugs in rats decreased after intravenous coadministration. Moreover, decreased uptake of the two drugs was observed in human kidney slices, rat kidney slices and hOAT1/hOAT3-transfected HEK293 cells when bestatin and cefixime were coadministered. The accumulation of bestatin and cefixime in kidney slices can be inhibited by p-aminohippurate, benzylpenicillin and probenecid, but not by tetraethyl ammonium. The results suggest that intestinal absorption and renal excretion of bestatin and cefixime can be inhibited when the two drugs were co-administered in rats. The pharmacokinetic mechanism indicates that the DDIs between bestatin and cefixime are mainly mediated by Pept1 and Oat1/3 in rats. PEPT1 and OAT1/3 are the target transporters of DDIs between bestatin and cefixime in human kidney slices and human transfected cells, proposing possible drug-drug interaction in humans.

[Cefixim: clinical pharmacology and role in therapy of urogenital infections].

Cefixim belongs to oral cephalosporins of the third generation and has the longest half-life period among all oral cephalosporins and, therefore can be taken once a day. Moreover, cefixim presents in high concentrations in the urine, kidneys and urinary tract. In vitro, this drug has high activity against basic pathogens of urogenital infection. A randomized clinical trial has found that cefixim has higher clinical and microbiological efficacy than ciprofloxacin in patients with acute uncomplicated cystitis.

Simultaneous determination of cefdinir and cefixime in human plasma by RP-HPLC/UV detection method: Method development, optimization, validation, and its application to a pharmacokinetic study.

A novel isocratic reversed-phase high performance liquid-chromatography/ultraviolet detection method for simultaneous determination of cefdinir and cefixime in human plasma was developed and validated after optimization of various chromatographic conditions and other experimental parameters. Sample preparation based on a simple extraction procedure consisting of deproteination and extraction with 3 parts of 6% trichloroacetic acid aqueous solution followed by volume make up with the aqueous component of the mobile phase obtained best recoveries of the two analytes. Samples were separated on a Supelco Discovery HS C(18) (150 mm × 4.6 mm, 5 µm) analytical column protected by a Perkin Elmer C(18) (30 mm × 4.6 mm, 10 µm) guard cartridge. The mobile phase, methanol/acetonitrile (50/50, v/v):0.05% trifluoroacetic acid (19:81, v/v), operated at 50°C column oven temperature was pumped at a flow rate of 2.0 mL min(-1) and the column eluents were monitored at a wavelength of 285 nm. When Sample was injected into the Perkin Elmer high performance liquid-chromatography system through Rheodyne manual (or auto-sampler) injector equipped with 20 µL loop, separation was achieved within 4 min. The present method demonstrated acceptable values for selectivity, linearity within the expected concentration range (0.004-5.0 µg mL(-1); r(2)>0.999 for both analytes), recovery (>95% for cefdinir and >96% for cefixime), precision (%RSD<2.0 for cefdinir and <2.2 for cefixime), sensitivity (limit of detection: 1 ng mL(-1) and lower limit of quantification: 4 ng mL(-1) for both analytes), stability of solutions, and robustness. The method was efficiently applied to a pharmacokinetic study in healthy volunteers.

Mechanism and implication of cephalosporin penetration into oropharyngeal mucosa.

The aim of this study was to explore the mechanism(s) by which oral cephalosporins penetrate into human oropharyngeal mucosa, and thus, the availability of sufficient concentrations at the site of infection. Two oral cephalosporin prototypes, cephalexin (first generation) and cefixime (third generation), were administered to five healthy subjects at two different visits with a 1-week washout period. Plasma and saliva samples were collected and drug concentrations were measured using an appropriate HPLC method. The maximum plasma concentrations (Cmax) of cefixime and cephalexin were 2.97+/-0.24 microg ml(-1) and 77.65+/-18.91 microg ml(-1), respectively. These concentrations were associated with a maximum salivary concentration (CSmax) of 0.56 microg ml(-1) for cefixime and 3.34 microg ml(-1) for cephalexin. Such levels exceed the reported minimal inhibitory concentration (MIC) for Streptococcus pyogenes and Streptococcus pneumoniae. The average concentration of cefixime in saliva corresponded to its plasma free fraction (saliva/plasma [S/P] ratio; 0.34). However, this observation was not true for cephalexin, for which antibiotic concentrations in the saliva did not appear to correspond to its plasma free fraction (0.8-0.85), with an S/P ratio of only 0.092. Our findings indicate that an active transport mechanism exists for cefixime excretion into human oropharyngeal mucosa, whereas cephalexin is passively diffused, although to a limited extent, as measured by its salivary concentrations.

Investigation of the role of oligopeptide transporter PEPT1 and sodium/glucose cotransporter SGLT1 in intestinal absorption of their substrates using small GTP-binding protein Rab8-null mice.

A small GTP-binding protein, Rab8, is essential for apical localization of oligopeptide transporter PEPT1/SLC15A1 and sodium/glucose cotransporter SGLT1/SLC5A1 in small intestine; deficiency of rab8 gene results in mislocalization and reduced expression of these transporters. Here, we examined the role of PEPT1 and SGLT1 in vivo in gastrointestinal absorption of a beta-lactam antibiotic, cefixime, and alpha-methyl-d-glycopyranoside (alpha-MDG), respectively, using rab8 gene knockout [rab8(-/-)] mice as experimental animals deficient in those transporters. Plasma concentration of cefixime and alpha-MDG after oral administration in rab8(-/-) mice was much lower than that in wild-type mice, whereas such reduction in oral absorption was not observed for antipyrine, membrane permeation of which is not transporter-mediated. Uptake of cefixime from the apical side of isolated small intestine assessed by means of the everted sac method in wild-type mice was decreased in the presence of excess unlabeled glycylsarcosine, a PEPT1 substrate. In contrast, the uptake in rab8(-/-) mice was much lower than that in wild-type mice and comparable with that of an extracellular marker, mannitol, suggesting that the apical membrane permeability of cefixime was reduced in rab8(-/-) mice. Uptake of cefixime in wild-type mice was pH-dependent, being higher at lower pH, whereas that in rab8(-/-) mice remained at the background level at all pH values examined. These results suggest that PEPT1 and SGLT1 play an important role in gastrointestinal absorption of cefixime and alpha-MDG, respectively, in vivo in mice. The present findings also illustrate the pharmacokinetic influence of the sorting machinery protein Rab8.

[Determination of cefixime blood plasma levels by HPLC].

For comparative study of the pharmacokinetics of Cemidexor (capsules of 100 mg) and Suprax (capsules of 400 mg), a method of HPLC with quantitative determination of cefixime (the active substance in the drugs) in the blood plasma of patients with UV detection was developed. The data teproducibility with an account of the admissibility criterion was observed within the interval of all the concentrations (0.06-10 mcg/ml). The accuracy and correctness of the method also corresponded to the admissibility criteria. The lower limit of the quantitative determimation of the cefexime blood plasma levels was 0.06 mcg/ml. The pharmacokinetics was studied with the open crossed randomized method. The results were used for calculation of the pharmacokinetic parameters required for estimation of the bioequivalence of the drugs. The statistical analysis of the pharmacokinetic parameters showed that Cemidoxor and Suprax were bioequivalent.

Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers.

The bioavailability of a new cefixime ((6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid, CAS 79350-37-1) tablet preparation (Loprax) was compared with that of a reference preparation of the drug in 24 healthy male volunteers. The trial was designed as an open, randomized, single-blind, two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 400 mg cefixime tablet as a test or reference formulation on 2 treatment days. The treatment periods were separated by a one-week washout period. The plasma concentrations of the drug were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-24h, AUC0-infinity, Cmax, t1/2, and Ke. The mean AUC0-infinity of cefixime was 45008.7 +/- 10989.9 and 45221.3 +/- 2155.7 n x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (Cmax) of cefixime was on average 4746.9 +/- 1284 ng/ml for the test and 4726.3 +/- 1206.9 ng/ml for the reference product. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for test and reference tablets. The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of Cmax, AUC0-infinity and AUC0-24h of cefixime were in the bioequivalence range (94%-112%). Therefore, the two formulations were considered to be bioequivalent.

Quantitative prediction of oral absorption of PEPT1 substrates based on in vitro uptake into Caco-2 cells.

The method for predicting the fraction absorbed (Fa) of the PEPT1 substrates was established based on the in vitro uptake into Caco-2 cells. Uptake of a drug into Caco-2 cells was measured, and the carrier-mediated initial uptake clearance (DeltaCL uptake) was calculated as the difference between the uptake clearance in the absence of glycyl-sarcosine (Gly-Sar) and that in the presence of 30 mM Gly-Sar. The DeltaCL uptake of each drug was then divided by that of cephradine to obtain DeltaCL*uptake, which was a normalized parameter to correct for inter-day and/or inter-cell variability. Then, cephradine (CED), cefixime (CFIX), and cefotiam (CTM) were selected as marker compounds having excellent, medium and poor absorption, respectively. The DeltaCL*uptake and Fa values for CED, CFIX and CTM were fitted to the equation derived from the complete radial mixing (CRM) model, and the scaling factor (A') was obtained. Using the A' value, Fa was predicted from the DeltaCL*uptake value of each drug. Good correlation was observed between the predicted and reported Fa values, which demonstrated that Fa of PEPT1 substrates can be predicted based on the in vitro uptake in Caco-2 cells.

[Efficacy of cefixime and cefepime vs. other cephalosporins in experimental plague of albino mice due to variants FI+ and FI- of the plague microbe].

Efficacy of cefixime and cefepime vs. ceftriaxone, cefotaxime, ceftazidime and cefoperazone was studied in vitro and in the treatment of experimental plague of albino mice due to natural, antigen complete strains of the plague microbe and the pathogen variants deprived of the ability to produce the capsule antigen fraction I (FI- phenotype). The MICs of cefixime and cefepime for 20 FI+ and 20 FI- strains of the plague microbe were 0.02-0.08 mg/l, that corresponded to the MICs of ceftriaxone, cefotaxime and ceftazidime. The MICs of cefoperazone were somewhat higher (0.1-0.2 mg/l). The ED50 values of cefixime and cefepime for prevention and treatment of experimental plague in mice statistically did not significantly differ from the ED50 values of ceftriaxone, cefotaxime, ceftazidime and cefoperazone. The efficacy indices (EIs) of cefixime and cefepime were > 10(4) independent of the infective strain phenotype (FI+ or FI-) and did not differ from those of ceftriaxone and ceftazidime. The efficacy of cefotaxime and cefoperazone was somewhat lower (EIs 1.7 x 10(3)-8.9 x 10(3)). Both the antibacterials were shown to provide high protective and therapeutic efficacy (80-100% of the survivors) independent of the phenotype (FI+ or FI-) of the pathogen infective strain. The results allowed to consider the antibiotics prospective in prevention and treatment of plague.

Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers.

This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bio-availability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC(0-t), AUC(0-infinity), Cmax, Kel, t1/2 and Cmax/AUC(0-infinity) were analyzed statistically using raw and log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pnfinity harmacokinetic parameters: AUC(0-t), AUC(0-infinity) Cmax, and Cmax/AUC(0-infinity) were within the range 80 - 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax, and Cmax/AUC(0-infinity) were 88.93 - 107.10%, 89.09 - 107.11%, 89.63 - 108.58% and 96.85 - 105.29%, respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), and Cmax using the Schuirmann's two one-sided t-tests. Therefore, the two formulations were considered to be bioequivalent.