Pharmacokinetics of Ketoprofen After Intravenous and Intramuscular Administrations to Rabbits

The pharmacokinetics of ketoprofen was studied in rabbits following intravenous and intramuscular administrations of ketoprofen, both at a dose of 4.0 mg.Kg^-1. Plasma levels of ketoprofen, as a function of time, were determined by a reversed-phase high performance liquid chromatography. The disposition of ketoprofen was described by a two-compartment open model with elimination from the central compartment. A model-independent method using the statistical moment theory was also applied. Pharmacokinetics of ketoprofen was characterized as a drug with terminal half-life of 3.15 hr, low apparent volumes of distribution (V = 0.031 L.Kg^-1, Vd_ss = 0.070 L.Kg^-1 and Vd_β = 0.130 L.Kg^c-1). The mean residence time (MRT) was found to be 1.44 hr for i.v. injection and 2.86 hr for i.m. injection. The clearance (CL) and apparent volume of distribution at steady state (Vd_ss) after i.v. injection was determined to be 0.027 L.Kg^-1.hr^-1 and 0.03 9 L.Kg^-1, respectively. The absorption rate constant from the limb muscle site into systemic circulation was calculated to be 2.19 hr^-1 and peak plasma concentration after i.m. injection was observed to be at 0.31 ± 0.11 hr. The systemic availability of ketoprofen after intramuscular administration was determined to be 0.38, relative to the equal i.v dose.     

Pharmacokinetics of Khellin in Rabbits: Oral,Intravenous, and Intramuscular Administrations

Abstract

This study was undertaken to investigate the pharmacokinetics of khellin in rabbits following oral, intravenous, and intramuscular administrations. Analysis of khellin in the plasma samples was performed according to a previously developed HPLC method. The data obtained from the rapid intravenous administration experiments fitted the two-compartment open model with β, α, total body clearance (TBC), and volume of central compartment (V_c) of 0.0306 hr^?1, 1.93 hr^?1, 573 ml. hr^?1.kg^?1, and 2.1 liter. kg^?1, respectively. The concentration-time profiles acquired following the administration of sugar-coated tablets of khellin were typical of sustained release formulations with time to peak concentration (t_max) and dose-normalized peak plasma concentration (C_max) of 21 hr and 23 ng. ml^?1.mg^?1.kg, respectively. With the exception of one animal, rapid absorption was obtained following the intramuscular or oral suspension administration with (t_max) ranging from 0.083 to 4 hr. A complete absorption was obtained with intramuscular injection, whereas, the fraction of dose absorbed following oral suspension administration was 38%.     

Effects of the Administration of Ketoprofen gel on the Percutaneous Absorption of Ketoprofen in Rabbits

The effects of the administration for a commercial keto-profen gel on the percutaneous absorption of ketoprofen (through rabbit abdominal skin) were investigated. The AUC (area under the curve) value of absorbed ketoprofen for single topical administration of 6 g of ketoprofen gel applied with ODT (occlusive dressing technique) was found to be about 6 -fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied with ODT at 6 h interval in a day. It was about 14-fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied without ODT at 6 h interval in a day. The experiment of volatilation of ketoprofen gels and the in vitro release test of ketoprofen gel applied with ODT and without ODT had been, in addition, respectively approached. The volatilation of solvent in the gel, as a result of this, may clearly be the primary factor for inducing a sharp descending of the plasma ketoprofen level following the Cmax (maximun concentration) in the in vivo percutaneous absorption of ketoprofen gel: this factor also results in a lower plasma ketoprofen level for the gel applied without ODT than that with ODT.     

Preparation and Pharmacokinetics in Rabbits of Breviscapine Unilamellar Vesicles

ABSTRACT

The purpose of the study was to prepare the unilamellar liposomal vesicles of breviscapine (Breviscapine-LUVs) and investigate the pharmacokinetics of Breviscapine-LUVs in rabbits. Breviscapine-LUVs were prepared by the film dispersion method and treated further by extrusion. Its size distribution and zeta potential were determined by photon correlation spectroscopy. The encapsulation efficiency (EE) and cumulative release of Breviscapine-LUVs were assayed by the dialysis method. The crossover design (two periods) was used in six rabbits, which were administered Breviscapine-LUVs and reference preparation. Results showed that the particle size of Breviscapine-LUVs was 50.8 nm, and the polydispersity index was 0.287. The zata potential was ?24 mV ± 9 mV(n = 3), and the EE% was 81.1 ± 1.1% (n = 3). The cumulative release of vesicles in 0.9% NaCl was 17.2 ± 0.78%, 26.1 ± 0.68%, and 29.9 ± 0.81% in 2, 8, and 24 h, respectively. The mean concentration-time curves of breviscapine liposomes and reference preparation were both fitted to a two-compartment model with the main pharmacokinetic parameters as follows: t_1/2β of Breviscapine-LUVs and reference preparation were (42.5 ± 28.6) min and (6.01 ± 4.64) min, respectively; CL_(s) were (15.3 ± 9.03) mL × min^?1 and (84.6 ± 40.6) mL × min^?1, respectively; AUC_0–300 were (1267 ± 1083) μg × min × mL^?1 and (196 ± 107) μg × min × mL^?1, respectively. Compared with the reference preparation, breviscapine liposomes had a much higher concentration in plasma and contained characteristic of sustained-release, which ameliorated the pharmacokinetic properties of scutellarin.     

Pharmacokinetics of Nilvadipine After Multiple Oral Dosing to Steady-State

Forty-four healthy male volunteers were randomly assigned to receive one of four dosing regimens: placebo or a dose of 6, 8, 10 or 12 mg of nilvadipine administered at 0, 7 and 14 hr each day for 19 doses over seven days. There was a proportional relationship between the maximum plasma concentration of nilvadipine after the first dose and the last dose and the dose administered. There was also a proportional relationship between the area under the plasma concentration-time curve during the last dosing interval and the administered dose. Results showed that there was no accumulation of drug in plasma at steady-state. In addition, there was no dose-dependency in the oral clearance, elimination rate constant or terminal elimination half-life values. The pharmacokinetics of nilvadipine are linear upon multiple dosign over the dosing range studied     

Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c₁₀–c₁₈) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c₁₀–c₁₈) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

Tissue Tolerance of Diclofenac Sodium Encapsulated in Liposomes After Intramuscular Administration

ABSTRACT

In this work the effect of the encapsulation of diclofenac sodium within liposomes on the reduction of the myotoxicity after intramuscular administration in rats was studied. Diclofenac sodium was encapsulated in small unilamellar liposomes obtained from phosphatidylcholine, cholesterol, and α-tocopherol (40:10:0.04 mM), and administered by intramuscular injection in the quadriceps femoral muscle of male Wistar rats. After a single dose of 0.2 mg diclofenac formulations the local tissue damage was assessed by plasma creatine kinase (CPK) activity and histological analysis. It was demonstrated that formulations containing free diclofenac produced a higher increase in CPK activity, while those encapsulated in liposomes exhibited CPK activity similar to the control groups. Histopathological analysis of local muscle tissue performed on the third and seventh days following the injection showed intense cellular damage when free drug solution was used, while encapsulation in liposome protected the tissue against the local tissue inflammation.     

Pharmacokinetics of Lignocaine in Humans After Peri-Oral Injections

Serum levels of lignocaine in ten healthy volunteers were determined after peri-oral injection of 36 mg lignocaine hydrochloride. Rapid absorption from injection site occured with a mean peak serum level of 46 ug/ml at 10 minutes.

In addition, lignocaine pharmacokinetics following peri-oral administration were studied. The serum concentration-time data were found to obey the one-compartment open model adequately with first-order absorption and elimination rates.     

Pharmacokinetics of Lignocaine in Humans After Peri-Oral Injections

Abstract

Serum levels of lignocaine in ten healthy volunteers were determined after peri-oral injection of 36 mg lignocaine hydrochloride. Rapid absorption from injection site occured with a mean peak serum level of 46 ug/ml at 10 minutes.

In addition, lignocaine pharmacokinetics following peri-oral administration were studied. The serum concentration-time data were found to obey the one-compartment open model adequately with first-order absorption and elimination rates.     

Intravenous Pharmacokinetics and in Vitro Protein-Binding Studies of two New Salts of Erythromycin

Abstract

Erythromycin pharmacokinetics were examined for two new salts of erythromycin, erythromycin melibionate and erythromycin penicillanate using erythromycin lactobionate for comparison, following intravenous injection to rabbits. The biological half-lives of erythromycin in serum were 99 minutes for erythromycin melibionate, 121 minutes for erythromycin penicillanate and 103 minutes for erythromycin lactobionate. Post intravenous administration serum erythromycin levels were adequately described by two compartment model kinetics, and values for the distribution volume of the central compartment and the overall distribution have been given. Estimated erythromycin distribution volumes may facilitate calculation of absorption efficiencies of erythromycin and its salts after oral doses. Serum protein binding study using horse serum showed that erythromycin melibionate, erythromycin penicillanate and erythromycin base were bound to the serum protein to the extent of 87.16%, 89.41% and 88.83% respectively; and released from the drug-protein complex to the extent of 11.25%, 8.66% and 10.66% respectively.     

Intravenous Pharmacokinetics and in Vitro Protein-Binding Studies of two New Salts of Erythromycin

Erythromycin pharmacokinetics were examined for two new salts of erythromycin, erythromycin melibionate and erythromycin penicillanate using erythromycin lactobionate for comparison, following intravenous injection to rabbits. The biological half-lives of erythromycin in serum were 99 minutes for erythromycin melibionate, 121 minutes for erythromycin penicillanate and 103 minutes for erythromycin lactobionate. Post intravenous administration serum erythromycin levels were adequately described by two compartment model kinetics, and values for the distribution volume of the central compartment and the overall distribution have been given. Estimated erythromycin distribution volumes may facilitate calculation of absorption efficiencies of erythromycin and its salts after oral doses. Serum protein binding study using horse serum showed that erythromycin melibionate, erythromycin penicillanate and erythromycin base were bound to the serum protein to the extent of 87.16%, 89.41% and 88.83% respectively; and released from the drug-protein complex to the extent of 11.25%, 8.66% and 10.66% respectively.     

Disposition of the Flavonoid Quercetin in Rats After Single Intravenous and Oral Doses

Abstract

The pharmacokinetic and mean time tissue distribution parameters, after a single 50-mg/kg dose of quercetin administered as intravenous bolus, oral solution, and oral suspension, were determined using rat as an animal model. Following intravenous administration, the elimination rate constant and the elimination half-life were found to be 0.0062 min^?1 and 111 min, respectively. Examining the mean time tissue distribution parameters reflected a strong binding affinity of the drug molecules to both plasma and tissue proteins. In addition, the low permeability rate of drug molecules in the peripheral system was demonstrated. Following the oral administration of the drug, the extent of absorption was greater from solution than from suspension. Moreover, the solution showed a shorter T_max and a higher C_max than suspension. The absolute bioavailability for the solution was 0.275 and that for suspension was 0.162. The mean residence time (MRT) and the mean absorption time (MAT) were higher for suspension, reflecting the need for dissolving the drug in order to be absorbed. The mean (in-vivo) dissolution time (MDT_in-vivo) was 34.5 min. Thus, an oral quercetin formulation that can readily form a drug solution in the gastrointestinal tract may enhance the absorption of the drug.     

The Dissolution and Complexing Properties of Ibuprofen and Ketoprofen when Mixed with N-Methylglucamine

The objectives of this study were to improve the aqueous dissolution properties of the poorly soluble nonsteroidal anti-inflammatory drugs ibuprofen and ketoprofen and to explore the use of N-methylglucamine (meglumine) to enhance the dissolution properties of poorly water-soluble drug powders. Changes in both differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) results indicate that possibly complexes were produced between ibuprofen and N-methylglucamine. Similar changes were not observed for equivalent ketoprofen and N-methylglucamine mixtures. The results of solubility and dissolution studies in water at 25°C and 37°C showed that N-methylglucamine, in mixtures and coprecipitates, increased the solubility, intrinsic dissolution, and powder dissolution of ketoprofen and ibuprofen. N-Methylglucamine significantly improved the solubility and dissolution properties of both ibuprofen and ketoprofen even when DSC and XRD behavior did not indicate the formation of complexes.     

Effects of Grinding with Microcrystalline Cellulose and Cyclodextrins on the Ketoprofen Physicochemical Properties

Ground mixtures of ketoprofen (KETO) with native crystalline β-cyclodextrin, amorphous statistically substituted methyl-β-cyclodextrin, and microcrystalline cellulose were investigated for both solid phase characterization (differential scanning calorimetry (DSC) powder X-ray diffractometry, and infrared (IR) spectrometry) and dissolution properties (dispersed amount and rotating disk methods) to evaluate the role of the carrier on the performance of the final product. The effects of different grinding conditions, partial sample dehydration, and 1 year storage at room temperature were also investigated. The results pointed out the importance of the carrier nature on the efficiency of the cogrinding process. Both cyclodextrins were much more effective than was microcrystalline cellulose, even though no true inclusion complex formation occurred by mechanochemical activation. The best results were obtained from ground mixtures with methyl-β-cyclodextrin, which showed the best amorphizing and solubilizing power toward the drug and permitted an increase of approximately 100 times its intrinsic dissolution rate constant, in comparison with the approximate 10 times increase obtained from ground mixtures with β-cyclodextrin.     

Development of Subcutaneous and Intramuscular Formulations of Calcium Alendronate Salts

Abstract

Poorly soluble calcium-alendronate salts were prepared and investigated as potential candidates for subcutaneous or intramuscular formulations. Three such formulations containing calcium-alendronate salts with different stoichiometries were developed for testing in safety, disposition and efficacy studies in animals. All formulations demonstrated a drastic reduction in pain on injection and tissue damaging propensity compared to the soluble salts of ABP. All three were efficacious and showed prolonged absorption from the injection site with the deposition of a large percentage of the dose into the bone. Complex formation between alendronate and calcium was also studied.     

Development of Subcutaneous and Intramuscular Formulations of Calcium Alendronate Salts

Poorly soluble calcium-alendronate salts were prepared and investigated as potential candidates for subcutaneous or intramuscular formulations. Three such formulations containing calcium-alendronate salts with different stoichiometries were developed for testing in safety, disposition and efficacy studies in animals. All formulations demonstrated a drastic reduction in pain on injection and tissue damaging propensity compared to the soluble salts of ABP. All three were efficacious and showed prolonged absorption from the injection site with the deposition of a large percentage of the dose into the bone. Complex formation between alendronate and calcium was also studied.     

Ketoprofen spray-dried microspheres based on Eudragit RS and RL: study of the manufacturing parameters

The preparation of ketoprofen spray-dried microspheres can be affected by the long drug recrystallization time. Polymer type and drug-polymer ratio as well as manufacturing parameters affect the preparation. The purpose of this work was to evaluate the possibility to obtain ketoprofen spray-dried microspheres using the Eudragit RS and RL; the influence of the spray-drying parameters on morphology, dimension, and physical stability of microspheres was studied. Ketoprofen microspheres based on Eudragit blend can be prepared by spray-drying and the nebulization parameters do not influence significantly particle properties; nevertheless, they can be affected by drying and storage methods. No effect of the container material is found.     

Characterization and Dissolution Properties of Ketoprofen in Binary and Ternary Solid Dispersions with Polyethylene Glycol and Surfactants

The effect of incorporation of an anionic [sodium dodecyl sulfate (SDS) or dioctylsulfosuccinate (DSS)] or nonionic [Tween 60 (TW60)] surfactant on the properties of ketoprofen solid dispersions in polyethylene glycol 15000 (PEG) has been investigated. Physicochemical and morphological properties of the various solid systems were determined by differential scanning calorimetry, hot stage microscopy, X-ray powder diffraction analysis, and scanning electron microscopy. The results from dissolution studies, performed according to the USP 24 basket method, indicated that all ternary dispersed systems were significantly (p < 0.001) more efficacious than the corresponding binary ones, by virtue of the additive wetting and solubilizing effect due to the presence of the surfactant. The relative effectiveness of the incorporated surfactant was in the same order as found in phase-solubility studies (i.e., SDS > DSS > TW60). With regard to the solid dispersion preparation method, coevaporated products always gave better results than the corresponding cofused ones; however, this effect was statistically significant (p < 0.001) only in the initial phase of the dissolution process. The most effective solid dispersion was the 10-80-10 w/w drug-PEG-SDS ternary coevaporate, which allowed dissolution of 50% drug after only 6 min (in comparison with > 120 min for drug alone and 17 min for the binary coevaporate) and dissolution of about 100% drug after 30 min (in comparison with > 120 min for the binary coevaporate).     

Comparative Pharmacokinetics of New Theophylline Preparations as Egifilin® 200 mg and 400 mg Retard Tablets After Single Dose in Healthy Volunteers

Pharmacokinetic properties of Egifilin® retard tablets (containing 200 or 400 mg of theophylline, EGIS Pharmaceuticals Ltd., Budapest, Hungary) were investigated in 12 healthy volunteers (six women, six men). Pharmacokinetic analysis was performed according to a one-compartment open model. The retard nature of both 200 and 400 mg tablets could be demonstrated. Comparison of the pharmacokinetic curves of women and men indicated that there was no sex difference in the pharmacokinetics of two retard tablets.

Egifilin retard tablets ensured plasma levels for almost 30 hr after single drug intake with an extremely long retard plateau between 6 and 30 hr. For study purposes, an improved rapid HPLC-UV analytical method (less than 3.5 min chromatogram) has been elaborated for the determination of theophylline in human plasma. The range of the calibration is 0.6-18 μg/ml.     

Pharmacokinetics and pharmacodynamics of dexmedetomidine

Dexmedetomidine is an alpha-2 adrenoceptor agonist and has been used as a general anesthetic, sedative and analgesic for about 30 years. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine, evaluate physiological factors that may affect the pharmacokinetics of dexmedetomidine, and summarize the pharmacodynamics of dexmedetomidine at different plasma levels. The pharmacokinetic parameters reported in previous studies according to noncompartmental analyses or population modeling results are compared. We concluded that the pharmacokinetic profile can be adequately described by a two-compartment model in population pharmacokinetic modeling. Body weight, height, albumin level, cardiac output, disease condition and other factors were considered to have significant influence on the clearance and/or distribution volume in different population pharmacokinetic models. The pharmacological effects of dexmedetomidine, such as sedation, heart rate reduction and biphasic change of blood pressure, vary at different plasma levels. These findings provide a reference for individualizing the dose of dexmedetomidine and achieving the desired pharmacological effects in clinical applications.