Plasma pharmacokinetics of melamine and a blend of melamine and cyanuric acid in rainbow trout (Oncorhynchus mykiss)

The objective of the study was to obtain pharmacokinetic parameters for melamine and blend of melamine (MEL) and cyanuric acid (CYA) in rainbow trout (Oncorhynchus mykiss). The single target dosage of MEL (20 mg/kg bw) and the blend of MEL and CYA (5 and 1.67 mg/kg bw, respectively) were designed and plasma samples were collected at 30 min, 1, 4, 8, 12, 20, 24, 36, 48, 72, 144 and 240 h sequentially. An optimized method for simultaneous determination of MEL and CYA in plasma and animal tissues by LC-MS/MS was used. The data were shown to best fit a non-compartment model with first order processes of linear characters for melamine, with half-life (t_1/2) of 32.2-32.9 h, clearance (Cl_z/F) of 35.9-36.6 ml/h/kg, and volume of distribution (V_ss) of 1.67-1.74 l/kg. Withdrawal of CYA was much more rapid than that of MEL with higher Cl_z/F (783.56 ml/h/kg) and shorter t_1/2 (7.92 h). T_max of MEL20 and MEL5 were 12 and 20 h, respectively, which showed that T_max of MEL5 was delayed when MEL and CYA were given together. The results are quite different from those in mammals and showed much slower elimination of MEL and CYA from rainbow trout body.     

Quantitation of the tacrine analogue octahydroaminoacridine in human plasma by liquid chromatography–tandem mass spectrometry

A rapid and sensitive method based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed for the determination of octahydroaminoacridine in human plasma using tramadol as internal standard (I.S.). Sample preparation involved pH adjustment with sodium carbonate followed by solvent extraction with dichloromethane:ethyl ether (40:60, v/v). Chromatographic separation was achieved on a Venusil MP-C18 column (5 μm, 100 mm × 4.6 mm) using acetonitrile:10 mM ammonium acetate:formic acid (30:70:1, v/v/v) as mobile phase. Detection utilized an API 4000 system operated in the positive ion mode with multiple reaction monitoring of the analyte at m/z 203.1 → 175.1 and of the I.S. at m/z 264.1 → 58.0. The method was linear in the range 0.01–10 ng/ml with a lower limit of quantitation of 0.01 ng/ml. Intra- and inter-day precisions measured as relative standard deviation were <3.15% and <5.01%, respectively. The method was successfully applied to a pharmacokinetic study involving oral administration of a tablet containing 4 mg octahydroaminoacridine succinate to healthy volunteers. Pharmacokinetic parameters for octahydroaminoacridine include C_max 1.19 ± 0.53 ng/ml, T_max 0.77 ± 0.17 h, AUC_0−t 3.42 ± 1.01 ng h/ml and t_1/2 2.89 ± 0.56 h.     

Quantification of the major metabolites of bromhexine in human plasma using RRLC–MS/MS and its application to pharmacokinetics

(E)-4-hydroxydemethylbromhexine (E-4-HDMB) and (E)-3-hydroxydemethylbromhexine (E-3-HDMB) were found as major metabolites, while (Z)-4-hydroxydemethylbromhexine and (Z)-3-hydroxydemethylbromhexine as minor metabolites of bromhexine in human plasma. These compounds were identified in comparison with synthetic authentic samples. A sensitive and selective rapid resolution liquid chromatography tandem mass spectrometry (RRLC–MS/MS) method was developed to quantify the concentration of bromhexine and its two major metabolites (E-4-HDMB and E-3-HDMB) in human plasma. Following solid phase extraction, the analytes were separated on a Zorbax 1.8 μm particle size reversed-phase C₁₈ column, using a gradient elution program with solvents consisting of 0.1% formic acid in acetonitrile and 0.1% formic acid in 5 mM ammonium acetate at a flow rate of 0.7 mL/min. Detection was carried out with an Agilent 6460 triple-quadrupole mass spectrometer operated with an electrospray ionization source mode operated in the positive ion mode. The recovery of bromhexine, E-4-HDMB, E-3-HDMB, and internal standard (IS) was 63.1–70.9%, 60.5–68.4%, 57.0–63.5%, and 87.8%, respectively. The matrix factors of bromhexine, E-4-HDMB, E-3-HDMB, and IS were 89.9–96.7%, 89.6–94.8%, 90.4–91.4%, and 103%, respectively. After an oral administration of 8.0 mg bromhexine to five healthy male subjects, AUC_0–24 h values of bromhexine, E-4-HDMB, and E-3-HDMB were found to be 93.5 ± 31.9, 34.0 ± 14.5, and 15.8 ± 6.89 ng h/mL, respectively; while C_max values were 24.6 ± 5.16, 3.11 ± 1.13, and 5.36 ± 2.55 ng/mL, respectively. Plasma concentration of bromhexine, E-4-HDMB, and E-3-HDMB declined with t_1/2 which gave 3.6 ± 0.5, 8.4 ± 2.7, and 6.4 ± 2.5 h, respectively.     

Quantification of cinacalcet by LC-MS/MS using liquid-liquid extraction from 50 μL of plasma

A simple and economical high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of cinacalcet in plasma. Following liquid-liquid extraction, the analyte was separated using an isocratic mobile phase on a reversed-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M+H]⁺ ions, m/z 358-155 for cinacalcet and m/z 310-148 for the internal standard. The assay exhibited a linear dynamic range of 0.1-200 ng/mL for cinacalcet in plasma. Acceptable precision (<10%) and accuracy (100 ± 5%) were obtained for concentrations over the standard curve range. A run time of 3.5 min for each sample made it possible to analyze more than 250 samples per day. The method was successfully applied to quantify cinacalcet concentrations in a preclinical pharmacokinetic study after a single oral administration of cinacalcet at 10 mg/kg to rats. Following oral administration the maximum mean concentration in plasma (C_max; 160 ± 56 ng/mL) was achieved at 1.0 h (T_max), area under the curve (AUC) and half-life (t_1/2) were 949 ± 257 ng h/mL and 3.58 ± 0.4 h, respectively.     

Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds

Objectives

Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An obidoxime plasma level in the range of 10–20 μM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients.

Methods

After admission to the intensive care unit (ICU) the obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24 h) was started and maintained as long as reactivation was possible. Plasma concentrations of obidoxime were determined by HPLC.

Results

A total amount of 2269 ± 1726 mg obidoxime was infused over 65 h ± 55 h resulting in a steady state plasma concentration of 14.5 ± 7.3 μM. Obidoxime was eliminated with t_1/2(1) 2.2 and t_1/2(2) 14 h. The volumes of distribution amounted to 0.32 ± 0.1 L/kg (V₍₁₎) and 0.28 ± 0.12 (V₍₂₎) L/kg. Postmortem examination of tissue in one patient showed obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration.

Conclusions

Using the suggested obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties.     

Determination of oxaceprol in rat plasma by LC–MS/MS and its application in a pharmacokinetic study

A sensitive method for the quantification of oxaceprol in rat plasma using high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) was developed. Sample pretreatment involved a simple protein precipitation by the addition of 60 μL of acetonitrile–methanol (1:2, v/v) to 20 μL plasma sample volume. Separation was achieved on a Dikma ODS-C18 (5 μm, 150 mm × 4.6 mm) reversed-phase column at 40 °C with acetonitrile/0.1% formic acid–4 mM ammonium acetate in water (35:65,v/v) at a flow rate of 0.6 mL/min. Detection was performed using an electrospray ionization (ESI) operating in negative ion multiple reaction monitoring (MRM) mode by monitoring the ion transitions from m/z 172 → 130 (oxaceprol) and m/z 153 → 109 (protocatechuic acid, internal standard). The calibration curve of oxaceprol in plasma showed good linearity over the concentration range of 1.25–800 ng/mL. The limit of detection and limit of quantification were 0.400 ng/mL and 1.25 ng/mL, respectively. Intra- and inter-day precisions in all samples were within 15%. There was no matrix effect. The validated method was successfully applied to a preclinical pharmacokinetic study of oxaceprol in rats. After oral administration of 20 mg/kg oxaceprol to rats, the main pharmacokinetic parameters T_max, C_max, T_1/2, V_z/F and AUC_0–t were 1.4 h, 1.2 μg/mL, 2.3 h, 19.7 L/kg and 3.4 mg h/L, respectively.     

Pharmacokinetics of prenylflavonoids and correlations with the dynamics of estrogen action in sera following ingestion of a standardized Epimedium extract

To explore pharmacokinetic properties of prenylflavonoids from the Traditional Chinese Medicinal plant Epimedium, three doses of a standardized extract (100, 300 and 600 mg/kg body weight), were administered to ovariectomized rats and serial blood samples were obtained. Serum concentrations of the Epimedium prenylflavonoids icariin, icariside I, icariside II, icaritin and desmethylicaritin were determined by LC–MS/MS. Aliquots of sera were also applied to human cell lines that permanently express ERα and ERβ proteins for the ex vivo measurement of estrogenic activity. All five prenylflavonoids exhibit non-linear dose-dependent increases in the area under concentration versus time curves. Two distinct pharmacokinetic patterns were evident, an early phase wherein icariin and icariside II reached t_max 0.5–1 h, and a late phase wherein icariside I, icaritin and desmethylicaritin peaked at t_max 8 h. Total concentrations of icaritin and desmethylicaritin reached C_max ∼2 μM and ∼0.25 μM respectively. Estrogenic activity in Epimedium-treated rat sera lagged by several hours compared to animals treated with control drug estradiol benzoate, corresponding to the appearance of bioactive metabolites desmethylicaritin, icaritin and icariside I. Following glucuronidase/sulphatase treatment, prolonged estrogenic activity at higher Epimedium doses (300 and 600 mg/kg of body weight) was evident, and correlated with the persistence of micromolar levels of icaritin at the 48–72 h sampling period. The depot effect resulted in time–concentration bioactivity profiles at the three Epimedium doses (area under curve 374, 543, and 771 pM E2 h⁻¹) that exceeded that observed for estradiol benzoate (148 pM E2 h⁻¹). Our study correlated the pharmacokinetics of prenylflavonoids with the dynamics of their estrogenic effects and reveals the potential estrogenicity of this Epimedium extract. This study may aid the development of prenylflavonoids as drugs for menopause and other conditions requiring estrogenic action.     

A high oxfendazole dose to control porcine cysticercosis: Pharmacokinetics and tissue residue profiles

Oxfendazole (OFZ) is efficacious for porcine cysticercosis at 30 mg/kg. OFZ is not registered to be used at this dose. The assessment of the OFZ and metabolites [(fenbendazole sulphone (FBZSO₂), fenbendazole (FBZ)] plasma pharmacokinetic and tissue residue profiles after its oral administration to pigs and the withdrawal period for human consumption were reported. Forty-eight pigs allocated into two groups received OFZ (30 mg/kg) orally as a commercial (CF) or as experimental formulation (SMF). Samples (blood, muscle, liver, kidney and fat) were collected over 30 days post-treatment and analyzed by HPLC. OFZ was the main compound recovered in plasma, followed by FBZSO₂ and low FBZ concentrations. OFZ AUC_0-LOQ (209.9 ± 33.9 μg·h/ml) and C_max (5.40 ± 0.65 μg/ml) parameters for the CF tended to be higher than those for the SMF (AUC_0-LOQ: 159.4 ± 18.3 μg h/ml, C_max: 3.80 ± 0.35 μg/ml). The highest total residue (OFZ + FBZSO₂ + FBZ) concentrations were quantified in liver, followed by kidney, muscle and fat tissue. FBZSO₂ residue levels were the highest found in muscle (0.68 ± 0.39 μg/g) and fat (0.69 ± 0.39 μg/g). In liver and kidney the highest residues corresponded to FBZ (5.29 ± 4.36 μg/g) and OFZ (2.86 ± 0.75 μg/g), respectively. A withdrawal time of 17 days post-treatment was established before tissues are delivered for human consumption.     

Plasma pharmacokinetics and tissue distribution study of cajaninstilbene acid in rats by liquid chromatography with tandem mass spectrometry

Cajaninstilbene acid (CSA; 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid) is a major active constituent of pigeonpea leaves, has been proven to be effective in clinical treatment of diabetes, hepatitis, measles and dysentery. A rapid and sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed and validated for the determination of CSA in rat plasma and various tissues (brain, heart, lung, liver, spleen, small intestine and kidney) of rat for the first time. Rat plasma and tissue distribution pre-treated by protein precipitation with acetoacetate was analyzed using LC–MS/MS with an electrospray ionization (ESI) interface, and isoliquiritigenin was used as an internal standard. Chromatographic separation was achieved on a HIQ Sil C₁₈ column with the mobile phase of water and methanol (9:91, v/v) containing 0.1% formic acid and resulted in a total run time of 10 min. The isocratic elution mode pumped at a flow rate of 1.0 mL/min. The lower limit of quantification (LLOQ) which was 10 ng/mL. The calibration curve was linear from 10 to 6000 ng/mL (R = 0.9967) for plasma samples and 10 to 6000 ng/mL (R ≥ 0.9974) for tissue homogenates. The intra- and inter-day assay of precision in plasma and tissues ranged from 0.6% to 6.1% and 1.5% to 6.6%, respectively, and the intra- and inter-day assay accuracy was 93.5–104.6% and 93.3–107.5%, respectively. Recoveries in plasma and tissues ranged from 95.0% to 106.8%. The method was successfully applied in pharmacokinetic and tissue distribution studies of CSA after oral administration to rats. The pharmacokinetics of CSA showed rapid absorption and elimination (T_max, 10.7 ± 0.31 min; t_1/2, 51.40 ± 6.54 min). After oral administration in rats, CSA was rapidly and widely distributed in tissues. High concentrations were found in liver and kidney indicating that CSA was possibly absorbed by liver and eliminated by kidney.     

A new approach for pharmacokinetics of single-dose cetuximab in rhesus monkeys by surface plasmon resonance biosensor

A novel assay method has been developed and validated, using surface plasmon resonance (SPR), for quantitation of cetuximab (C225) in monkey serum. By injecting non-labeled antibody samples onto a biosensor surface on which epidermal growth factor receptor (EGFR) was immobilized, the concentration of C225 can be accurately measured. This assay has a range of reliable response from 0.05 to 50 μg/ml C225 in monkey serum, which was well fitted with a sigmoidal model. The immobilized EGFR was found to be stable for at least 100 regeneration cycles at room temperature. Intra- and inter-assay CVs ranged from 3.20% to 8.89% and from 5.93% to 11.11%, accuracy from 92% to 107.52% and from 90% to 106.88%, respectively. Matrices such as 50% human serum, 50% Sprague Dawley rat serum, chimeric recombinant anti-CD20 monoclonal antibody, human γ-globulin and chimeric recombinant her2 antibody did not interfere with C225 analysis on the sensor surface. This is the first report on the quantitation of C225 in monkey serum by an optical biosensor technology. This method was used to characterize the pharmacokinetics of C225 in rhesus monkeys. After a single-dose of intravenous infusion administration of 7.5, 24 and 75 μg/kg, average C_max ranged from 168 ± 28 to 1624 ± 113 μg/ml, and AUC_0–∞ ranged from 15,739 ± 1059 to 295,017 ± 44,533 μg h/ml. C225 elimination followed a bi-exponential profile with t_1/2 ranging from 2.7 ± 0.7 to 6.7 ± 0.1 h. It was non-linear serum pharmacokinetics of C225 across the investigated dosage range in monkeys (7.5–75 mg/kg).     

Pharmacokinetic and tissue distribution of doxycycline in broiler chickens pretreated with either: Diclazuril or halofuginone

Following IV injection of doxycycline in a dose of 20 mg kg⁻¹ b.wt., its serum concentration was best fitted in two-compartment open model in chickens fed either on control or on anticoccidials-containing rations. Diclazuril and halofuginone resulted in a significant short distribution half-life (t_½α) (7.17 ± 0.39 and 11.88 ± 1.05 min, respectively) and increased total body clearance (Cl_tot) 0.37 ± 0.024 and 0.295 ± 0.034 L/kg/h, respectively. Following oral dosing the tested drug absorbed with t_½ab of 41.38 ± 1.6, 17.48 ± 0.86 and 41.83 ± 1.8 min, respectively and their C_max values (3.18 ± 0.18, 5.425 ± 0.48 and 0.986 ± 0.037 μg/ml) were attained at 2.07 ± 0.097, 1.403 ± 0.074 and 2.55 ± 0.106 h. For doxycycline alone and in presence of diclazuril and halofuginone, respectively. Systemic bioavailability was 22.64 ± 3.46, 86.74 ± 9.23 and 22.38 ± 3.09%, respectively. Following IM injection t_½ab were 9.096 ± 1.34 for doxycycline alone, 16.24 ± 2.21 and 15.6 ± 1.7 min in the presence of diclazuril and halofuginone, respectively. C_max was 3.10 ± 0.28, 4.63 ± 0.57 and 0.55 ± 0.07 μg/ml reached at 0.8 ± 0.083, 1.13 ± 0.126 and 1.21 ± 0.105 h. For the antibiotic alone, and in presence of either diclazuril and halofuginone, respectively. Systemic bioavailability was 22.41 ± 3.86, 88.97 ± 12.9 and 12.31 ± 0.99% in chickens fed on anticoccidial-free, diclazuril- and halofuginone-containing rations, respectively. Both the tested anticoccidials induced higher doxycycline tissue residues in all tested tissue samples.     

Higher than recommended amikacin loading doses achieve pharmacokinetic targets without associated toxicity

Antibiotic therapy improves the outcome of severe sepsis and septic shock, however pharmacokinetic properties are altered in this scenario. Amikacin (AMK) is an option to treat community or nosocomial infections, although standard doses might be insufficient in critically ill patients. The aim of this study was to evaluate two AMK dosage regimens in comparison with standard therapy with regard to efficacy in achieving adequate plasma levels as well as safety. In total, 99 patients with severe sepsis or septic shock were randomised to different AMK dose protocols: Group 1, 25 mg/kg/day; Group 2, 30 mg/kg/day; and Group 3, historical standard dose (15 mg/kg/day). Peak plasma concentrations at 1 h (C_max) were determined. Pharmacokinetics was determined and renal function was monitored to evaluate toxicity. Groups were compared using bilateral T-test. Demographic characteristics of the three groups were comparable. AMK C_max values were 57.4 ± 9.8, 72.1 ± 18.4 and 35.2 ± 9.4 μg/mL, respectively (P < 0.001 between Groups 1 and 2 versus Group 3, and P < 0.01 between Group 1 versus Group 2). A C_max > 60 μg/mL was reached by 39%, 76% and 0% of patients in Groups 1, 2 and 3, respectively (P < 0.001) and creatinine clearance at Day 28 was 95.6 ± 47.4, 89.7 ± 26.6 and 56.4 ± 18.4 mL/min, respectively. In conclusion, a 30 mg/kg daily dose of AMK presents significantly higher C_max compared with the other groups, with 76% of patients reaching recommended peak plasma levels with no association with higher nephrotoxicity. Standard doses are insufficient in critically ill patients to reach the recommended C_max.     

Plasma disposition and tissue depletion of difloxacin and its metabolite sarafloxacin in the food producing animals, chickens for fattening

Chickens were used to investigate plasma disposition of difloxacin after single intravenous (IV) and oral dose (10 mg/kg body weight (BW)) and to study residue depletion of difloxacin and its major metabolite sarafloxacin after multiple oral doses (10 mg difloxacin/kg BW, daily for 5 days). Plasma and tissue samples were analyzed using a HPLC method. After IV and oral administration, plasma drug concentration-time curves were best described by a two-compartment open model. Mean (± SD) elimination half-lives (t_½β) of difloxacin were 9.53 ± 1.00 and 12.23 ± 1.81 h after IV and oral administration. Maximum plasma concentration was 2.34 ± 0.50 μg/ml and interval from oral administration until maximal concentration was 1.34 ± 0.03 h. Oral bioavailability was found to be 68.89 ± 15.21%. Difloxacin was converted to sarafloxacin. After multiple oral dose (10 mg difloxacin/kg BW, daily for 5 days), mean kidney, liver, muscle and skin + fat tissue concentrations of difloxacin and sarafloxacin ranging between 604.8 ± 132.5 and 368.1 ± 52.5 μg/kg and 136.4 ± 18.3 and 10.4 ± 1.2 μg/kg, respectively, were measured 1 day after administration of the final dose of difloxacin. A withdrawal time of 5 days was necessary to ensure that the residues of difloxacin were less than the maximal residue limits (MRL) or tolerance established by the European Union.     

Depletion of melamine and cyanuric acid in serum from catfish Ictalurus punctatus and rainbow trout Onchorhynchus mykiss

Melamine and its triazine analogs, such as cyanuric acid, have been used to artificially inflate protein content both in animal feed ingredients, as well as in milk products produced for human consumption. We report here a LC–MS/MS method to quantify and confirm melamine and cyanuric acid in serum from channel catfish and rainbow trout with a limit of quantification of 0.8 μg/mL. The method was applied to serum samples from a residue depletion study in which fish were given a single oral dose of 20 mg/kg body weight melamine, cyanuric acid, or both compounds together. Samples were taken at 1, 3, 7, 14, and 28 days (an additional 42 day was added for trout). When given alone or in combination with cyanuric acid, melamine residues were highest on day 1 in both catfish and trout. Cyanuric acid was only quantifiable at day 1 in trout when given alone, and not at all in catfish. The serum half life of melamine in catfish was 1.50–1.62 days and 3.09–3.67 days in trout. This work highlights the differences of depletion kinetics in fish, which can be measured in days, as compared to the depletion in mammals, measured in hours.     

Ultra high-pressure liquid chromatographic assay of moxifloxacin in rabbit aqueous humor after topical instillation of moxifloxacin nanoparticles

The present report describes a rapid and sensitive ultra high-pressure liquid chromatography (UHPLC) method with UV detection to quantify moxifloxacin in rabbit aqueous humor. After deproteinisation with acetonitrile, gradient separation of moxifloxacin was achieved on a Waters Acquity BEH C18 (50 mm × 2.1 mm, 1.7 μm) column at 50 °C. The mobile phase consisted of 0.1% trifluoroacetic acid in water and acetonitrile at a flow rate of 0.4 ml/min. Detection of moxifloxacin was done at 296 nm. Method was found to be selective, linear (r = 0.9997), accurate (recovery, 97.30–99.99%) and precise (RSD, ≤1.72%) in the selected concentration range of 10–1000 ng/ml. Detection and quantitation limit of moxifloxacin in aqueous humor were 0.75 and 2.5 ng/ml, respectively. The aqueous humor levels of moxifloxacin after single topical instillation in three formulations, i.e. moxifloxacin solution (Moxi-SOL), anionic nanoparticles (Moxi-ANP) and cationic nanoparticles (Moxi-CNP) were investigated. A fourfold increase in the relative bioavailability was observed with the Moxi-CNP (AUC_0→t, 3.14 μg h/ml) compared with Moxi-SOL (AUC_0→t, 0.79 μg h/ml) and Moxi-ANP (AUC_0→t, 0.72 μg h/ml) formulation. The results indicate that the cationic nanoparticle increases ocular bioavailability of moxifloxacin and prolong its residence time in the eye.     

Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy

We prepared fast dissolving oral thin film that contains dexamethasone and base materials, including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40 °C and 75% in humidity for up to 24 weeks. The film was disintegrated within 15 s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min. Subsequently, pharmacokinetic properties of dexamethasone were compared in rats with oral administration of 4 mg dexamethasone suspension or topical application of the film preparation containing 4 mg dexamethasone to the oral cavity. Pharmacokinetic parameters were similar between the two groups in which C_max (h), T_max (μg/mL), AUC (μg/mL/h) and half-life (h) were 12.7 ± 6.6 (mean ± SD, N = 10), 3.4 ± 1.4, 93.6 ± 37.8 and 1.66 ± 0.07, respectively, for oral suspension and 13.3 ± 4.0, 3.2 ± 1.0, 98.0 ± 22.3 and 1.65 ± 0.06, respectively, for film preparation. These findings suggest that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.     

In vitro and in vivo iontophoretic transdermal delivery of an anti-parkinsonian agent

To objective of this work was to study the feasibility of iontophoretic delivery of SLV 318 (7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone methanesulfonate) across hairless rat skin in vitro and in vivo. The effect of counter-ions and temperature were investigated for optimizing SLV 318 solubility. The effect of electrode efficiency and total current applied on the delivery of SLV 318 were studied using Franz diffusion cells and samples were analyzed using HPLC. Delivery increased with increasing concentration. For current-time combinations, electrode had to be replaced every 9 h. Passive, iontophoretic (0.1 mA/cm² for 1 h) and intravenous studies were performed in vivo. Blood samples collected were analyzed using LC-MS/MS. SLV 318 had higher solubility with NaCl (75 mM) as a counter-ion at 25 °C than with other counter-ions tested. In vivo iontophoresis significantly enhanced the permeation and also reduced its lag time (P < 0.05). The C_max of SLV 318 during 1 h iontophoresis was 6.56 ± 0.68 ng/mL at 1.31 ± 0.29 h (T_max) as compared to 2.96 ± 0.29 ng/mL at 25.32 ± 0.67 h (T_max) by 24 h passive permeation. The in vitro and in vivo data has shown the feasibility to enhance delivery of SLV 318 by iontophoresis.     

Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100

The in vivo pharmacokinetics/pharmacodynamics of 2′-O-(2-methoxyethyl) (2′-MOE) modified antisense oligonucleotides (ASOs), targeting apolipoprotein B-100 (apoB-100), were characterized in multiple species. The species-specific apoB antisense inhibitors demonstrated target apoB mRNA reduction in a drug concentration and time-dependent fashion in mice, monkeys, and humans. Consistent with the concentration-dependent decreases in liver apoB mRNA, reductions in serum apoB, and LDL-C, and total cholesterol were concurrently observed in animal models and humans. Additionally, the long duration of effect after cessation of dosing correlated well with the elimination half-life of 2′-MOE modified apoB ASOs studied in mice (t_1/2 ≅ 20 days) and humans (t_1/2 ≅ 30 days) following parental administrations. The plasma concentrations of ISIS 301012, observed in the terminal elimination phase of both mice and monkeys were in equilibrium with liver. The partition ratios between liver and plasma were similar, approximately 6000:1, across species, and thus provide a surrogate for tissue exposure in humans. Using an inhibitory E_max model, the ASO liver EC_50s were 101 ± 32, 119 ± 15, and 300 ± 191 μg/g of ASO in high-fat-fed (HF) mice, transgenic mice containing the human apoB transgene, and monkeys, respectively. The estimated liver EC₅₀ in man, extrapolated from trough plasma exposure, was 81 ± 122 μg/g. Therefore, extraordinary consistency of the exposure-response relationship for the apoB antisense inhibitor was observed across species, including human. The cross-species PK/PD relationships provide confidence in the use of pharmacology animal models to predict human dosing for second-generation ASOs targeting the liver.     

Enhanced distribution and extended elimination of glycyrrhetinic acid in mice liver by mPEG-PLA modified (mPEGylated) liposome

A rapid and simple method of high-performance liquid chromatography with UV detector for the quantification of glycyrrhetinic acid (GA) in mice plasma and tissues has been developed and validated. With the established assay method, the pharmacokinetic profiles and tissue distribution of GA in different formulations are compared in mice after intravenous administration of the drug (25 mg/kg). The results showed that mPEG-PLA modified (mPEGylated) GA liposome (PL-GA) significantly prolonged the mean residence time (MRT) of GA in mice plasma and liver (MRT: 0.43 ± 0.13 and 1.72 ± 0.11 h, respectively) than the normal GA liposome (L-GA) (MRT: 0.23 ± 0.01 and 1.07 ± 0.31 h, respectively) and GA sodium injection (S-GA) (MRT: 0.13 ± 0.01 and 0.95 ± 0.08 h, respectively). Moreover, PL-GA specifically increased GA uptake in liver (AUC_{0–∞,liver} value of 1.6-fold and 1.3-fold higher than that for S-GA and L-GA, respectively) and reduced its distribution into other tissues after dosing. Due to these pharmacokinetic properties, it may be promising to develop PL-GA further as a new pharmaceutical preparation for GA on the treatment of various chronic hepatic diseases.