Pharmacokinetic Study In Rabbits Research Articles

QbD-Oriented Development and Characterization of Effervescent Floating-Bioadhesive Tablets of Cefuroxime Axetil

The objective of the present studies was systematic development of floating-bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% > 6h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance.

Extended release and enhanced bioavailability of moxifloxacin conjugated with hydrophilic cellulose ethers

Macromolecular prodrugs (MPDs) of moxifloxacin were fabricated based on hydroxypropylcellulose (HPC) and hydroxyethylcellulose (HEC). UV/Vis spectrophotometry was employed to determine covalently loaded drug content (DC) of each conjugate. The degree of substitution (DS) of moxifloxacin attained ranged from 0.27 to 0.38 (HPC) and 0.19 to 0.26 (HEC) per anhydroglucose unit (AGU), respectively. Transmission electron microscopic analyses showed that HPC–moxifloxacin conjugates self-assembled into nanowires of ∼30nm diameters while HEC–moxifloxacin conjugates self-assembled into nanoparticles of 150–350nm. In vitro drug release studies revealed that 15 and 49% moxifloxacin release occurred from the HPC–moxifloxacin conjugate after 6h at pH 1.2 and 7.4, respectively. Similarly, moxifloxacin release from HEC–moxifloxacin conjugates was 15 and 39% at pH 1.2 and 7.4, respectively. Bioavailability and pharmacokinetic studies in rabbits showed that both HPC- and HEC-conjugates exhibited significantly enhanced moxifloxacin plasma half-life, over 24h, confirming sustained release and enhanced bioavailability (AUC 2.0–2.1 times higher) of moxifloxacin.

Preparation and Evaluation of Diclofenac Sodium Tablet Coated with Polyelectrolyte Multilayer Film Using Hypromellose Acetate Succinate and Polymethacrylates for pH-Dependent, Modified Release Drug Delivery.

Polyelectrolyte multilayer (PEM) film formed due to the electrostatic interaction between oppositely charged polyelectrolytes is of considerable interest because of their potential applications as both drug carriers and surface-modifying agents. In this study, in vitro studies were carried out on polyelectrolyte complexes formulated with Eudragit E (EE) and hypromellose acetate succinate (HPMCAS). The complexes of EE and HPMCAS were formulated by non-stoichiometric method. The prepared IPCs were investigated using Fourier transform infrared spectroscopy. Diclofenac sodium (DS) tablets were prepared and were coated with polymer solution of HPMCAS and EE to achieve pH-dependent and sustained-release tablets. Tablets were evaluated for their physical characteristics and in vitro drug release. The results of pharmacokinetic studies in rabbits showed that the selected formulation (F6) exhibited a delayed peak plasma concentration and marked sustained-release effect of drug in the in vivo drug release in comparison with marketed tablet. The suitable combination of PEM film based on EE and HPMCAS demonstrated potential candidate for targeted release of DS in the lower part of the gastrointestinal (GI) tract.

Aprepitant loaded solid preconcentrated microemulsion for enhanced bioavailability: A comparison with micronized Aprepitant

Aprepitant (APT) is a lipophilic, poorly water soluble drug with moderate permeability characteristic. Therefore, we aimed to improve solubility as well as permeability that could possibly improve oral bioavailability of APT. For this purpose, Quality by design (QbD) approach employing simplex lattice mixture design was used to prepare solid preconcentrated microemulsion (S-PCM). Further, the software generated numerically optimized S-PCM formulations were developed by utilizing desirability function. The spectral attributes (powder X-ray diffraction, ATR-FTIR, and differential scanning calorimetry) of S-PCM formulations suggested that APT was present in amorphous form. The results of droplet size (150–180nm), zeta potential (−13 to −15mV), poly dispersity index (PDI) (0.211–0.238) and emulsification time (<1min), of these S-PCM formulations (SP1, SP2 and SP3) suggested spherical shape morphology (Transmission electron microscopy) with thermodynamic stability. The comparison of in vitro/ex vivo behavior of S-PCM (SP1) with micronized and non-micronized formulations of APT suggested 2-fold and 5-fold enhancement in solubility and permeability, respectively. This was further evident from pharmacokinetic studies in rabbits that showed 1.5-fold enhancement in bioavailability of S-PCM with respect to micronized APT. Thus, it could be envisaged that development of S-PCM formulation of APT is the best alternative to micronization technology based APT formulations reported earlier.

Comparative bio-safety and in vivo evaluation of native or modified locust bean gum-PVA IPN microspheres

Strategically developed natural polymer-based controlled release multiparticulate drug delivery systems have gained special interest for “spatial placement” and “temporal delivery” of drug molecules. In our earlier study, locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (LBG-PVA IPN), carboxymethylated locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (CMLBG-PVA IPN) and acrylamide grafted locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (Am-g-LBG-PVA IPN) were prepared and characterized. The present study deals with accelerating stability testing, comparative bio-safety and single dose in vivo pharmacokinetic study of all three IPN microspheres for controlled oral delivery of buflomedil hydrochloride (BH). From the stability study, it was observed that the particles were stable throughout the study period. From toxicity and biodegradability study it was proved that the microspheres were safe for internal use and complied with bio-safety criterion. From the in vivo pharmacokinetic study in rabbits, it was observed that the CMLBG-PVA IPN microspheres possessed almost similar Tmax value with BH oral suspension. However, in comparison between the LBG-PVA and Am-g-LBG-PVA IPN microspheres, the later showed well controlled release property than the first in biological condition. Thus, this type of delivery system might be useful to achieve the lofty goals of the controlled release drug delivery.

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.

Preparation of goreisan suppository and pharmacokinetics of trans-cinnamic acid after administration to rabbits.

Goreisan suppository is prepared as a hospital preparation, and successfully used for the treatment of diarrhea and vomiting in young children with common cold. While clinical efficacy of the suppository has been reported, few studies have been carried out to clarify the preparation procedure and pharmacokinetics of the suppository. In this study, trans-cinnamic acid (CA) was used as a representative substance of goreisan constituents, and assayed by HPLC-UV. We investigated the properties of goreisan suppositories prepared using various sizes of pulverized goreisan extract granules, in vitro dissolution profiles using the reciprocating dialysis tube method, and pharmacokinetics in rabbits compared with those for goreisan enema. Mass and content uniformity tests on the suppositories of three size fractions, 0-75, 75-150, and 150-300 µm, showed good acceptance for all kinds of suppository. Storage stability at 4°C was maintained until 4 months. In vitro dissolution of CA from the suppository was proportional to time until 45 min, and slower than that from the enema. Finally, 80% of CA had dissolved at 60 min. Pharmacokinetic study in rabbits revealed that the area under the plasma concentration-time curve from 0 to 120 min (AUC0-120 min) of the suppository was twice that of the enema. Moreover, from a study in rabbits using CA injection and CA suppository, we revealed that CA was rapidly and well absorbed from the rectum, showing 84% absolute bioavailability. Thus, we illustrated the defined preparation procedure of the suppository and the superiority of the suppository over the enema. This study will support evidence that the suppository is fast-acting and efficacious in clinical use.

Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization

Intranasal thermosensitive gel for rasagiline mesylate (RM) was developed for effective treatment of Parkinson’s disease. Intranasal gels were prepared by combination of poloxamer 407 and poloxamer 188 (1:1) with mucoadhesive polymers (carbopol 934 P and chitosan). The formulations were evaluated for sol–gel transition temperature, in-vitro drug release and in-vivo mucociliary transit time. Further, optimal intranasal gel formulations were tested for in-vivo pharmacokinetic behavior, nasal toxicity studies and brain uptake studies. It was found that optimal formulations had acceptable gelation temperature (28–33 °C) and adequate in-vitro drug release profile. Pharmacokinetic study in rabbits showed significant (p < 0.05) improvement in bioavailability (four- to six-folds) of the drug from intranasal gels than oral solution. Chronic exposure studies in Wistar rats showed that these intranasal gels were non-irritant and non-toxic to rat nasal mucosa. Estimation of RM in rat brain tissue showed significant (p < 0.01) improvement in uptake of RM form intranasal gel formulations than nasal solution.

Simple and Rapid Determination of Zafirlukast in Plasma by Ultra-performance Liquid Chromatography Tandem Mass Spectrometric Method: Application into Pharmacokinetic Study in Rabbits

Zafirlukast is a selective leukotriene receptor antagonist used for the prophylaxis and chronic treatment of asthma. The aim of the present study was to develop a simple sensitive ultra-performance liquid chromatography tandem mass spectroscopy method for rapid determination of zafirlukast in plasma. After a simple one step protein precipitation by acetonitrile, zafirlukast and montelukast (IS) were separated on Acquity UPLC BEH(TM) C18 column (50 × 2.1 mm, i.d. 1.7 µm, Waters, USA) using a mobile phase of acetonitrile:water containing 10 mM acetic acid (80:20, v/v) at a flow rate of 0.3 mL/min. Zafirlukast and IS were eluted at 0.51 and 1.1 min, respectively with a total run time of only 1.5 min. The mass spectrometric determination was carried out using an electrospray interface operated in the negative mode with multiple reactions monitoring mode. The precursor to product ion transitions of m/z 574.11>462.07 and m/z 584.2>472.1 were used to quantify zafirlukast and IS, respectively. The method was linear in the concentration range of 0.17-600 ng/mL with coefficients of determination greater than 0.996 and lower limit of quantitation of 0.17 ng/mL. Intra-day and inter-day accuracies were 88.3-113.9% and the precisions were ≤ 12.6%. Zafirlukast was found to stable under various storage and sample processing conditions as per guidelines of bio-analytical method validation. The method developed herein is simple and rapid, and was successfully applied for the pharmacokinetic study in rabbits.

Microwave-induced solid dispersion technology to improve bioavailability of glipizide

The effect of microwave (MW) irradiation and conventional heating (CH) on solid dispersion (SD) of poorly water-soluble glipizide (GPZ) and polyethylene glycol 4000 (PEG 4000) were studied in detail. The chemical stability of GPZ on exposure to MW irradiation and CH was confirmed by high-performance liquid chromatography, Fourier transform infra red spectroscopy, proton nuclear magnetic resonance and mass spectroscopy studies. Comparative bioavailability studies were performed in rabbits using glipizide sustained-release tablets prepared using MW irradiation (MW-SD) or CH (CH-SD), with Glytop 2.5 mg SR as a reference. The MW-assisted melt mixing showed higher efficiency than CH in obtaining a homogeneous mixture having glass transparency. The polymorphic transformation of GPZ in each case was further confirmed by powder X-ray diffraction study. The solubility of GPZ in phosphate buffer pH 6.8 was greater for MW-SD (72.250 ± 0.154 μg/ml) than CH-SD (46 ± 0.201 μg/ml). The MW-SD matrix tablet (2.5 mg) displayed retarded drug release (releasing 99.320 ± 4.992% drug in 12 h). In-vivo pharmacokinetic study in rabbits revealed that the relative bioavailability of GPZ from MW-SD tablets improved greatly (153.73 ± 9.713%). MW-induced SD technology could be a better alternative to CH-SD for the enhanced solubility and bioavailability of GPZ.

Thymoquinone-loaded nanostructured lipid carriers: preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration

BackgroundNanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers. Thymoquinone is the main bioactive compound of Nigella sativa. In this study, the preparation, gastroprotective effects, and pharmacokinetic (PK) properties of thymoquinone (TQ)-loaded NLCs (TQNLCs) were evaluated.MethodTQNLCs were prepared using hydrogenated palm oil (Softisan® 154), olive oil, and phosphatidylcholine for the lipid phase and sorbitol, polysorbate 80, thimerosal, and double distilled water for the liquid lipid material. A morphological assessment of TQNLCs was performed using various methods. Analysis of the ulcer index, hydrogen concentration, mucus content, and biochemical and histochemical studies confirmed that the loading of TQ into the NLCs significantly improved the gastroprotective activity of this natural compound against the formation of ethanol-induced ulcers. The safety of TQNLC was tested on WRL68 liver normal cells with cisplatin as a positive control.ResultsThe average diameter of the TQNLCs was 75 ± 2.4 nm. The particles had negative zeta potential values of −31 ± 0.1 mV and a single melting peak of 55.85°C. Immunohistochemical methods revealed that TQNLCs inhibited the formation of ethanol-induced ulcers through the modulation of heat shock protein-70 (Hsp70). Acute hepatotoxic effects of the TQNLCs were not observed in rats or normal human liver cells (WRL-68). After validation, PK studies in rabbits showed that the PK properties of TQ were improved and indicated that the drug behaves linearly. The Tmax, Cmax, and elimination half-life of TQ were found to be 3.96 ± 0.19 hours, 4811.33 ± 55.52 ng/mL, and 4.4933 ± 0.015 hours, respectively, indicating that TQ is suitable for extravascular administration.ConclusionNLCs could be a promising vehicle for the oral delivery of TQ and improve its gastroprotective properties.

Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop.

The eye has protective barriers (ie, the conjunctival and corneal membranes) and defense mechanisms (ie, reflex tearing, blinking, lacrimal drainage) which present challenges to topical drug delivery. Topical ocular corticosteroids are commonly used in the treatment of anterior segment diseases and inflammation associated with ocular surgery, and manufacturers continually strive to improve their characteristics. We describe the development of a novel ophthalmic gel formulation of loteprednol etabonate (LE), a C-20 ester-based corticosteroid with an established safety profile, in the treatment of ocular inflammatory conditions. The new LE gel formulation is non-settling, eliminating the need to shake the product to resuspend the drug, has a pH close to that of tears, and a low preservative concentration. The rheological characteristics of LE gel are such that the formulation is instilled as a drop and transitions to a fluid upon instillation in the eye, yet retains sufficient viscosity to prolong ocular surface retention. The new formulation provides consistent, uniform dosing as evidenced by dose extrusion studies, while pharmacokinetic studies in rabbits demonstrated rapid and sustained exposure to LE in ocular tissues following instillation of LE gel. Finally, results from two clinical studies of LE gel in the treatment of postoperative inflammation and pain following cataract surgery indicate that it was safe and effective. Most patients reported no unpleasant drop sensation upon instillation, and reports of blurred vision were rare.

Anticancer activity, toxicity and pharmacokinetic profile of an indanone derivative

The present study describes anticancer effect of gallic acid based indanone derivative (1). Indanone 1 exhibited in vivo anticancer activity against Erhlich ascites carcinoma in Swiss albino mice by inhibiting tumor growth by 54.3% at 50mg/kg b.wt. It showed antitubulin effect by inhibiting tubulin polymerase enzyme. In cell cycle analysis, it inhibited G2/M phase and induced apoptosis. It significantly suppressed VEGF-R1, VEGF-R2 and HIF-α in human breast cancer MCF-7 cells, thus exhibiting antiangiogenic activity. In acute oral toxicity, indanone 1 was well tolerated and was found to be non-toxic up to 1000mg/kg b.wt. in Swiss albino mice. Pharmacokinetic studies in rabbits revealed rate of absorption, half life, volume of distribution with high plasma and blood clearance after i.v. administration. Indanone 1, is a safe and moderately active anticancer agent.

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization, in vitro and in vivo pharmacokinetic studies

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 32 factorial design was done using Polyox WSR 303 (X1) and HPMC K4M (X2) as independent variables and cumulative percentage drug released at 6 h (Q6h) as dependent variable.Results: Optimized formulation showed floating lag time of 4–5 s, floated for more than 12 h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6 h. In vivo pharmacokinetic studies in rabbits showed Cmax of 189.96 ± 13.04 ng/mL and Tmax of 4 ± 0.35 h for GFDDS. The difference for AUC(0–T) and AUC(0–∞) between the test and reference formulation was statistically significant (p > 0.05). AUC(0–T) and AUC(0–∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively.Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.

LC Method for Determination of Rasagiline Mesylate in Different Plasma Matrices and its Application to Oral Pharmacokinetic Study in Rabbits

A simple, rapid and sensitive reverse-phase liquid chromatographic method is developed and validated for estimation of rasagiline mesylate in different plasma matrices (rat, rabbit and human plasma). The method employs an isocratic elution technique with a Kromasil C18 column and has an optimized mobile phase composition of 10 mM ammonium acetate buffer-acetonitrile (40:60 v/v). The plasma samples displayed linear detector responses in the concentration range of 0.5-20 µg/mL in all plasma matrices when monitored at 265 nm using an ultraviolet detector. Because the simple protein precipitation method yields over 95% recovery of rasagiline mesylate from all plasma matrices, no internal standard was used in this method. A detailed validation study of the method proves the accuracy, precision and selectivity (in estimating rasagiline mesylate) in all plasma matrices. The drug is also stable under various processing and storage conditions in all plasma matrices, as evident from the study. The present method was applied to determine the drug-protein binding ratio in all the plasma matrices. The use of this method in determining pharmacokinetic parameters of rasagiline mesylate by non-compartmental analysis after oral dosing in rabbits is also discussed.

Biopolymeric mucoadhesive bilayer patch of pravastatin sodium for Buccal delivery and treatment of patients with atherosclerosis

Mucoadhesive bilayer buccal patch has been developed to improve the bioavailability and therapeutic efficacy along with providing sustained release of pravastatin sodium. Buccal patches comprising of varying composition of Carbopol 934P and HPMC K4M were designed and characterized for surface pH, swelling index, in vitro bioadhesion, mechanical properties, in vitro drug release and in vivo pharmacokinetic and pharmacodynamics performance. All formulations exhibited satisfactory technological parameters and followed non-fickian drug release mechanism. Bilayer buccal patch containing Carbopol 934P and HPMC K4M in 4:6 ratio (PBP5) was considered optimum in terms of swelling, mucoadhesion, mechanical properties and in vitro release profile. Pharmacokinetic studies in rabbits showed significantly higher (p < 0.05) Cmax (75.63 ± 6.98 ng/mL), AUC0-8 (311.10 ± 5.89 ng/mL/h) and AUC0-∞ (909.42 ± 5.89 ng/mL/h) than pravastatin oral tablet (Cmax – 67.40 ± 9.23 ng/mL, AUC0-8-130.33 ± 10.25 ng/mL/h and AUC0-∞-417.17 ± 5.89 ng/mL/h)). While, increased tmax of buccal patch indicated its sustained release property in comparison to oral tablet. Pharmacodynamic studies in rabbits showed statistically significant difference (p < 0.005) in the reduction of TG (131.10 ± 10.23 mg/dL), VLDL (26.00 ± 2.56 mg/dL) and LDL level (8.99 ± 3.01 mg/dL) as compared to oral conventional tablet. In conclusion, bioavailability from the developed buccal patch of pravastatin was 2.38 times higher than the oral dosage form, indicating its therapeutic potential in the treatment of atherosclerosis.

Mucoadhesive bilayer buccal tablet of carvedilol-loaded chitosan microspheres: in vitro, pharmacokinetic and pharmacodynamic investigations

A multiple-unit system comprising mucoadhesive bilayer buccal tablets of carvedilol-loaded chitosan microspheres (CMs) was developed to improve bioavailability and therapeutic efficacy of carvedilol. Drug-loaded CMs were prepared by spray drying, evaluated for powder and particle characteristics, and optimized batch of CMs was compressed into bilayer buccal tablets using Carbopol. Tablets were evaluated for physicochemical parameters, in vitro drug release, in vivo pharmacokinetic and pharmacodynamic studies. Optimized formulation, CMT1 (CMT, chitosan microsphere tablet) showed maximum mucoadhesive force (50 ± 1.84 dyne/cm2), exhibited 73.08 ± 3.05% drug release and demonstrated zero-order kinetics with non-Fickian release mechanism. Pharmacokinetic studies in rabbits showed significantly higher Cmax (71.26 ± 6.45 ng/mL), AUC0–10 (AUC, area under the curve 390.75 ± 5.23 ng/mL/h) and AUC0–∞ (664.72 ng/mL/h) than carvedilol oral tablet. Pharmacodynamic studies confirmed reduction in mean arterial pressure, heart rate, body weight and triglyceride on administration of bilayer buccal tablet compared to oral carvedilol tablet. Multiple-unit system exhibited enhanced bioavailability and sustained release of carvedilol, indicating its improved therapeutic potential for the treatment of hypertension.

Effect of levofloxacin on lithium – a pharmacokinetic study in rabbits

The aim of this study was to evaluate potential drug-drug interaction between lithium and levofloxacin. The study was conducted on New Zealand white rabbits with three groups having two subgroups each (n = 12). The first group compared the pharmacokinetic (Pk) parameters of lithium when lithium was given as a single dose (56 mg/kg) and when lithium was co-administered with levofloxacin (35 mg/kg). The second group compared the Pk parameters of lithium when lithium was given for 6 days alone and when levofloxacin was given on the sixth day after lithium steady-state levels were achieved. The third group compared the Pk parameters of lithium when lithium was given alone for 8 days and levofloxacin was given on days 6, 7, and 8 along with lithium. Apart from this, creatinine levels were also measured to detect nephrotoxicity effects because of this co-administration. It was found that there was increase in lithium levels in all three groups. The increase was significant when a single dose of levofloxacin was administered with steady-state level of lithium (C(max) of lithium: 2.54 ± 0.15 vs 2.79 ± 0.12 mm, P < 0.001 and AUC(0-α) of lithium: 24.36 ± 3.68 vs 31.88 ± 4.83 mmol/mL h, P < 0.001). The increase in lithium levels was also significant when levofloxacin was coprescribed for 3 days after lithium steady-state levels were achieved (C(max) increased from 2.72 ± 0.29 to 3.96 ± 0.29 mm, P < 0.001 and AUC(0-α) increased from 27.1 ± 4.96 to 42.64 ± 4.94 mmol/mL h). Levofloxacin increases lithium levels when they are co-administered, and this interaction might be clinically significant as they may be coprescribed.

Simultaneous Determination of Benzimidazoles and Their Metabolites in Plasma Using High-Performance Liquid Chromatography/Tandem Mass Spectrometry: Application to Pharmacokinetic Studies in Rabbits

An HPLC/MS/MS method was developed for the simultaneous determination of the following benzimidazole anthelmintics and metabolites in plasma: flubendazole, albendazole, fenbendazole, mebendazole, thiabendazole, hydrolyzed flubendazole, albendazole sulfoxide, albendazole sulfone, albendazole aminosulfone, oxfendazole, fenbendazole sulfone, aminomebendazole, hydroxymebendazole, and 5-hydroxythiabendazole. The sample preparation process involved a pH-dependent extraction of the analytes. Chromatographic separation was performed on a C18 column with a mobile phase gradient starting with methanol-water (20 + 80, v/v) containing 0.1% formic acid. The overall average recoveries of the analytes based on a matrix-matched calibration ranged from 75.0 to 120.0%, with RSD values of <20.0%. The LODs ranged from 0.08 to 2.0 microg/kg and the LOQs from 0.3 to 5.0 microg/kg. The validated method was used in pharmacokinetic studies of benzimidazole compounds in rabbits, and the elimination of the metabolites was measured quantitatively.

Rapid-onset sildenafil nasal spray carried by microemulsion systems: in vitro evaluation and in vivo pharmacokinetic studies in rabbits

An oleic acid-based microemulsion system with a member of the Tween series or Cremophor EL as the surfactant and a short-chain alcohol as the cosolvent was developed for rapid-onset intranasal delivery of sildenafil.The phase behaviour and solubilization capacity of the microemulsion system were characterized, and nasal absorption of sildenafil from the microemulsion formulations was investigated in rabbits.Sildenafil displayed a high solubility of 124 mg/mL in the microemulsion consisting of 40% oleic acid, 10% H2O, and 50% Tween 80:ethanol (EA) (at a 1:4 weight ratio). Nasal absorption of sildenafil from this microemulsion was found to be fairly rapid. With a 10-mg dose, the onset of action was arrived instantly following intranasal administration and the duration was over 3 h using an in vivo rabbit studies. In addition, nasal ciliotoxicity studies were carried out using in vivo rat nasal mucosa model and showed no ciliotoxicity. Therefore, the prepared systems are no serious nasal ciliotoxicity for intranasal administration.The microemulsion system composed of oleic acid, Tween 80, EA, and water may be a practical approach for the rapid-onset delivery of sildenafil for the treatment of erectile dysfunction.