Elimination Half-time Research Articles

Effects of Pegylated Glucagon-Like Peptide-1 Analogue in C57Bl/6 Mice under Optimal Conditions and During Streptozotocin-Induced Diabetes.

Biological activity of a new pegylated form of an of glucagon-like peptide-1 (GLP-1) analogue pegGLP-1 was studied in C57Bl/6 mice under normal conditions and during modeling of streptozotocin-induced type I diabetes mellitus. pegGLP-1 differs from GLP-1 (7-37) by polyethylene glycol residue covalently bound to His7, Lys26, and Lys34 of the GLP-1 molecule. It was shown that single intragastrical administration of pegGLP-1 induced an increase in GLP-1 level in blood serum of healthy mice. The maximum level of this parameter was observed in 4-8 h. pegGLP-1 elimination half-time was 8.5 h and mean retention time was 15 h. Administration of pegGLP-1 to animals with modeled type I diabetes mellitus was followed by an increase in the levels of GLP-1 and insulin in blood serum, produced a hypoglycemic effect, and improved the parameters of glucose-tolerance test. Biological activity of pegGLP-1 was higher than activity of GLP-1.

Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication

Paliperidone prolongs cardiac repolarization in a concentration-dependent manner. Meanwhile, continuous infusion of intravenous lipid emulsion (ILE) has been established as a detoxification therapy for lipophilic drugs. However, this change in pharmacokinetics of various drugs following ILE administration remains to be clarified. Our objective is to clarify the effect of continuous infusion of ILE on the pharmacokinetics of overdosed paliperidone in rats. Paliperidone (20mg/kg) was administered orally to free-moving male Wistar rats. Continuous infusion (initial loading dose: 4ml/kg for 10min, followed by 4ml/kg/h for 12h) of ILE or acetated Ringer's solution (AR) was initiated 30min after paliperidone administration. Plasma concentration profile of paliperidone was monitored for 12h after administration. The plasma concentration and tissue/plasma concentration ratios of paliperidone were compared between ILE and AR groups. The rat group infused with ILE showed a higher area under the concentration–time curve (mean [S.D.]: 6102 [900.9] vs. 3407 [992.1]nghml−1, p=0.02) and longer elimination half-time (t1/2) (4.1 [0.9] vs. 2.2 [0.4]h, p=0.02) compared with the AR group. Tissue/plasma concentration ratios of paliperidone were lower in ILE rats than in AR rats (1.98 [0.70] vs. 3.82 [1.47] in the heart, p=0.04; 0.28 [0.29] vs. 1.27 [0.58] in the brain, p<0.001). In conclusion, continuous infusion of ILE would reduce tissue distribution and prolonged the t1/2 of paliperidone in rats. These results suggest that continuous infusion of ILE has potential as an emergency treatment for acute paliperidone intoxication.

TINJAUAN AKUMULASI SEFTRIAKSON DARI DATA URIN MENGGUNAKAN ELEKTROFORESIS KAPILER PADA PASIEN GANGGUAN FUNGSI GINJAL STADIUM TIGA

&lt;p&gt;Ceftriaxone is a third-generation cephalosporin which are excreted mostly via the kidneys. Drugs which are eliminated primarily by the kidneys may accumulate in the patients with impaired renal function. Ceftriaxone is widely used in DR.M.Djamil Hospital Padang. The dosage adjustment for this drug has not yet performed in the hospital so far. This study was conducted in patients who suffered from stage 3 renal failure, received ceftriaxone therapy, and were 20-65 years of age. Urine samples were collected from patients at 4, 4.5, 5.75, 6.5, 7.75, and 8.25 hours after drug administration. Samples were analyzed using capillary electrophoresis. The buffer used was sodium tetraborate with pH of 9, concentration of 50 mM and pKa 9,24. The absorbance of solutions were measured at wavelength of 241.2 nm. From the standard calibration curve of ceftriaxone, the equation of Y = 4.455x - 2.297 (R&lt;sup&gt;2&lt;/sup&gt; = 0.995), (SD =1.40) was obtained. The migration time of ceftriaxone was 9 minutes. The LOD and LOQ were 0.94 and 3.14 µg/mL, respectively. The elimination rate and elimination half life were 0.046/h and 15,06 h, respectively. D&lt;sub&gt;u&lt;/sub&gt; cumulative and acumulation fraction of drugs were 365.10 mg and 0.33 (33%), respectively. D&lt;sub&gt;max&lt;/sub&gt; and D&lt;sub&gt;min&lt;/sub&gt; were 2.985 and 985 mg, respectively. C&lt;sub&gt;max&lt;/sub&gt; and C&lt;sub&gt;min&lt;/sub&gt; were 224,43 and 74,06 mg/L, respectively. The accumulation index of the drug was 1.49. Cl. AUC&lt;sub&gt;0&lt;/sub&gt;&lt;sup&gt;˜&lt;/sup&gt; and the Cp&lt;sup&gt;O&lt;/sup&gt; were 0.612 L/h, 3.268 mg h/L and 150.37 mg/L, respectively. Impaired renal function may affect pharmacokinetic parameters such as elimination rate, elimination half-time, and drug clearance.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;&lt;p&gt; &lt;/p&gt;

DETERMINATION OF CISPLATIN IN HUMAN BLOOD PLASMA AND URINE USING LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY FOR ONCOLOGICAL PATIENTS WITH A VARIETY OF FATTY TISSUE MASS FOR PREDICTION OF TOXICITY

The research was aimed to analyze a level of triglycerides in blood serum as a possible new marker of toxicity, particularly in patients with excess body weight, receiving cisplatin. Study involved 20oncological patients with stage III lung cancer, who received palliative treatment with cisplatin. High-performance liquid chromatography was used for quantitative determination of pure cisplatin in urine and blood samples. Cisplatin concentration of the test samples was determined based on the data obtained from the calibration graph. Quantitative determination of pure cisplatin is quite complicated. The elimination half-time for one of the groups was observed higher almost by half than for other patients. Higher dose of cisplatin showed a significant association with increase in triglyceride levels. We found a close correlation between body mass index and triglyceride changes during chemotherapy (p = 0.001; r = 0.67). The results indicate that a higher body mass index gives higher fluctuations of triglyceride levels in blood serum. Analyses of correlation between level of triglycerides and elimination half-time show that by an increase in the level of triglycerides in the blood serum cisplatin elimination half-time is prolonged (R2Linear=0.596). Cisplatin concentration in urine is higher and elimination takes longer time at elevated levels of triglycerides, where close correlation between fraction of excreted substance in urine and concentration parameters was seen (p < 0.01). Also good correlation for body mass index with fraction of excreted substance in urine and concentration parameters was observed (p<0.05). Clearance of cisplatin, which was determined by the chromatographic method, is reduced in individuals with increased adipose tissue mass. Research data suggest that overweight affects cisplatin elimination from the body. The greater body fat mass can contribute to a greater rise of triglyceride level in blood serum. Triglycerides in blood plasma may serve as an additional indicator of higher cisplatin toxicity as a cardiotoxicity marker.

Analysis of Pharmacokinetic Interaction Between Amiodarone/Desethylamiodarone and Metoprolol

Amiodarone (AM) is the most effective antiarrhythmic drug and its major metabolite desethylamiodarone (DEA) is pharmacologically effective as well. A β1 blocker metoprolol (M) is metabolized to alpha-hydroxymetoprolol (OH-M) by CYP2D6 and both AM and DEA inhibit this enzyme. We analysed interaction between amiodarone/ desethylamiodarone and metoprolol. We analyzed retrospectively 69 serum concentrations of AM, DEA, M and OH-M measured by HPLC method with UV or fluorescent detection from 29 patients (years 2014-2015). We estimated the concentration/dose ratio of metoprolol, metabolic ratio of M/OH-M and OH-M/M, and metoprolol clearance (Cl) and elimination half-time (t1/2) depending on concentrations of AM, DEA and sum AM+DEA. Phenotypization of patients was performed by metabolic ratio (MR) of M/OH-M concentrations. Statistically significant correlation was observed between concentration/dose ratio of metoprolol and concentrations of both AM and DEA as well as between metabolic ratio M/OH-M and concentrations of both sum AM+DEA and DEA itself. No statistically significant correlation was found between t1/2 a Cl of metoprolol and concentrations of AM or DEA. Phenotypization of CYP2D6 divided individual samples into groups with MR<1.0 (n=17) and MR 1.0-10.5 (n=7) for serum taking after metoprolol administration and with MR<1.0 (n=31) and MR 1.0-10.5 (n=7) for serum taking before metoprolol administration. We showed that an increasing concentrations of amiodarone and desethylamiodarone led to lower dose of metoprolol to achieved the same serum concentration. Increase of DEA and sum of AM+DEA concentrations led to decrease of metoprolol metabolization by inhibition of CYP2D6. The results indicate that important drug-drug interaction between metoprolol and amiodaron is due to inhibition of CYP2D6, mainly by DEA. Therefore wen the combination of drugs is administered careful therapeutic monitoring of not only metoprolol but also of amiodarone including DEA is recommended.

Kinetic modeling of the retention and fate of inhaled cerium oxide nanoparticles in rats: The cumulative displacement volume of agglomerates determines the outcome

This paper compares the pulmonary kinetics of inhaled nano-CeO2 from published repeated inhalation studies of 1-, 4-, 13-, and 52-week duration using a previously published kinetic model to simulate the pulmonary kinetics of inhaled micron-sized poorly soluble, low toxicity particles (PSPs) in rats. This comparative analysis demonstrates that the kinetic hallmarks characterizing lung overload-related pulmonary inflammation are indistinguishable for PSPs and agglomerated nano-CeO2. Unlike PSPs, nano-CeO2 appears to dissolve within the lung as long as tissue saturation has not been attained. When saturation is reached, the accumulated retained particle displacement volume becomes the prominent unifying factor interrelating the retained volumetric particle dose and pulmonary inflammogenicity observed in inhalation studies of 1- to 52-weeks duration. In summary, the pulmonary kinetics of nano-CeO2 inhaled as micron-sized agglomerates exhibit kinetic and toxicological profiles similar to micron-sized PSPs. The coherence of modeled and empirical outcomes supports the hypothesis that the leading metric of pulmonary toxicity is the displacement volume of accumulated aggregated particles. Whereas agglomerated nano-CeO2 particles follow the typical kinetic of lung overload, evidence of dissolution of nano-CeO2 demonstrates a much shorter elimination half-time of t1/2 = 17 days. Thus, kinetic modeling approaches appear to not only deliver the highest degree of integrated mechanistic information, it also provides a validating feed-back loop to verify/refute the starting hypothesis of inhalation studies.

Hyperventilation with Maintenance of Isocapnia. An “Old New” Method in Carbon Monoxide Intoxication

IntroductionExposure to carbon monoxide (CO) is among the most common causes of acute and chronic poisonings worldwide. The crucial point of treatment of such acute poisonings is to eliminate CO from the body as fast as possible. There are currently two approaches to the management of the CO intoxication: hyperbaric oxygen therapy (HOT) and normobaric oxygen therapy (NOT). HOT is highly effective and capable of achieving the CO elimination half-time (T½) as low as 15 minutes. Unfortunately this method is expensive and not always readily available. The elimination of CO with the use of NOT (T½~70 min) is slower, but treatment can be started even on the site of the exposure and continued while the patient is transported to a hospital. The aim of the study was to evaluate the effectiveness of a method using therapeutic hyperventilation with maintenance of isocapnia (IH) in the elimination of CO in volunteers exposed to CO and to compare selected gasometric and respiratory parameters during IH with the values obtained during hyperventilation with pure oxygen (“non-isocapnic hyperventilation”–NIH).Material and methodsThe study involved 13 healthy, chronically-smoking volunteers. Each of them participated in two independent hyperventilation tests: IH and NIH. The levels of carboxyhemoglobin (COHb) and selected gasometric, cardiac and respiratory parameters were measured at 0, 10 and 20 minutes during both tests. Among 13 volunteers (8 women and 5 men) the initial COHb level was 5.0±1.5% (mean±SD) before the IH tests and 5.1±1.9% before the NIH tests (p>0.05). After 20 minutes of the procedures the mean COHb level was 2.9±0.9% for IH and 3.6±1.2% for NIH (p<0.01). The T½ of COHb was 29.6±12.2 min and 47.3±19.2 min respectively (p<0.01). After 10 minutes of NIH respiratory alkalosis was noted in 11 participants (84.6%). Such problem was not seen during the IH procedures. No serious adverse effects were recorded during either IH or NIH. Mild symptoms such as: dyspnea, headache and paresthesias were reported by 6 volunteers (46%) during both IH and NIH tests. It is worth noting that paresthesias were only reported during NIH, by 2 participants (15.4%).ConclusionsThe elimination T½ of CO during IH was comparable with the values reported during HOT, and lower than can be achieved with NOT or NIH. No serious adverse effects were reported during IH procedures. Further studies, especially direct comparisons with NOT and HOT, are necessary to evaluate the effectiveness of IH in the treatment of acute CO poisoning.

Sedation for Pediatric Patient with End-Stage Hepatic Disease Outside Operating Room

Sedation outside operating room for children has increasing importance. Pediatric patients with end stage liver disease are of great importance for various and frequent procedures including gastrointestinal endoscopy, magnetic resonance imaging, computerized tomography, brachytherapy, catheterisation, interventional radiology. Anesthesia plan plays critical role for the success of these procedures. Patient safety, ventilation, hemodynamic responses, side effects of anesthetics on liver and periprocedural analgesia are the main topics of attention. Airway management tools may be helpful because of edema and ascites pushing diaphragm upwards. Nasal capnography enables monitoring spontaneous ventilation. Enlargement of extravascular extracellular fluid and dysproteinemia, effects drug behaviors. Drug elimination half-time as well as context sensitive half-time have to be taken into account and designed individually. The pressure above vena cava inferior, results with decrease in preload, thus reduction in cardiac output. Pulse wave variation monitoring helps for estimating circulating fluid status. Tendency for bleeding can be anticipated with fresh frozen plasma. Patient-controlled analgesia may be a choice of favor but close monitoring required for repeated analgesics. Children's Hospital of Eastern Ontario Pain Scale would be a good monitoring tool for pain.

SN-38 loading capacity of hydrophobic polymer blend nanoparticles: formulation, optimization and efficacy evaluation

One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipitation, as a simple one-step procedure with good reproducibility and FDA approved polymers like Poly(lactic-co-glycolic acid) (PLGA) and Polycaprolactone (PCL), will only potentiate this issue. Considering that drug loading is one of the key defining characteristics, in this study we attempted to examine whether the nanoparticle (NP) core composed of two hydrophobic polymers will provide increased drug loading for 7-Ethyl-10-hydroxy-camptothecin (SN-38), relative to NPs prepared using individual polymers. D-optimal design was applied to optimize PLGA/PCL ratio in the polymer blend and the mode of addition of the amphiphilic copolymer Lutrol®F127 in order to maximize SN-38 loading and obtain NPs with acceptable size for passive tumor targeting. Drug/polymer and polymer/polymer interaction analysis pointed to high degree of compatibility and miscibility among both hydrophobic polymers, providing core configuration with higher drug loading capacity. Toxicity studies outlined the biocompatibility of the blank NPs. Increased in vitro efficacy of drug-loaded NPs compared to the free drug was confirmed by growth inhibition studies using SW-480 cell line. Additionally, the optimized NP formulation showed very promising blood circulation profile with elimination half-time of 7.4 h.

Preclinical Pharmacokinetics and Toxic Kinetics Study of 2, 4-Dinitrophenol (DNP)

1.1. Purpose: To research the pharmacokinetics and tissue distribution of 2,4-dinitrophenol (DNP) in tumor-bearing mice and the pharmacokinetics and toxicokinetics in beagle dogs. 1.2. Methods: a. Pharmacokinetics in tumor-bearing mice: DNP was administrated intra tumorally to the mice with three different dosages, the drug concentration and tissue distribution were determined by the HPLC at different time, then analyze the pharmacokinetic parameters. b. Pharmacokinetics in beagle dogs: DNP was intravenously administrated in forelimb with three different dosages and drug concentrations were determined in dog’s plasma before and after each injection to calculate pharmacokinetic parameters. c. Toxicokinetics: the beagle dogs received intramuscular injection for two weeks and the plasma on the first day and the 13th day after the treatment were collected for the toxicity evaluation. 1.3. Results: i. DNP showed the characteristics of linear dynamic when administrated intra temporally in mice from the dosage of 8mg/kg to 32mg/kg. DNP was widely distributed with the relative targets including liver, kidney and lung. ii. Pharmacokinetics in beagle dogs: both of the elimination half time (T1/2) and the area under curve (AUC) of DNP increased with the increasing dose of DNP, showed the characteristics of non-linear dynamics. The systemic toxicity increased with the increasing dose of DNP, showed the characteristics of linear dynamics after multiple injections. No drug accumulation or sex differences happened in beagle dogs. 1.4. Conclusion: DNP is a relatively safe agent, showing the characteristics of linear dynamics after intratumor and intramuscular injection. Thus, the study provides reference for the clinical application.

Pharmacokinetics of the MRI contrast agent gadobutrol in common marmoset monkeys (Callithrix jacchus)

This study determined the pharmacokinetics of the contrast agent gadobutrol in marmosets by quantitative MRI to derive guidelines for neuroimaging protocols. Local concentrations of gadobutrol were determined from consecutive gradient echo-based mapping of the relaxation rate R1 on a clinical 3T MRI scanner. Half-time of renal elimination was measured after injection of a triple dose of gadobutrol (0.3mmol/kg) into the saphenous vein. A first-order single-compartment model was fitted to the measured R1 values and verified by blood analysis. Slow injection (1.5minutes) resulted in an elimination half-time of 26±4minutes. After bolus injection (15seconds), elimination was much slower (62±8minutes) with 45% larger distribution volumes. Importantly, more gadobutrol entered the cerebrospinal fluid. Slow injection and a latency of about 20minutes are recommended to avoid extravasation. Application of a triple dose of gadobutrol compensates for the fast elimination in healthy marmosets.

Therapeutic efficacy and effects of artesunate-amodiaquine and artemether-lumefantrine on malaria-associated anaemia in Nigerian children aged two years and under.

BackgroundArtemisinin-based combination therapies are recommended as first-line treatments for uncomplicated falciparum malaria, but there is little evaluation of their efficacy and effects on uncomplicated malaria-associated anaemia in children aged 2 years and under.MethodsParasitological efficacy and effects on malaria-associated anaemia were evaluated in 250 malarious children aged 2 years and under, and efficacy was evaluated in 603 malarious children older than two but younger than 5 years of age following treatment with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL). Kinetics of the disposition of parasitaemia following treatment were evaluated using a non-compartment model. Late-appearing anaemia (LAA) was diagnosed using the following criteria: clearance of parasitaemia, fever and other symptoms occurring within 7 days of starting treatment, adequate clinical and parasitological response on days 28–42, haematocrit (HCT) ≥ 30 % at 1 and/or 2 weeks, a fall in HCT to < 30 % occurring at 3–6 weeks, absence of concomitant illness at 1–6 weeks, and absence of asexual parasitaemia detected using both microscopy and polymerase chain reaction (PCR) at 1–6 weeks.ResultsOverall, in children aged 2 years and under, the PCR-corrected parasitological efficacy was 97.2 % (95 % CI 92.8–101.6), which was similar for both treatments. In children older than 2 years, parasitological efficacy was also similar for both treatments, but parasite prevalence 1 day after treatment began was significantly higher, and fever and parasite clearance times were significantly faster in the AA-treated children compared with the AL-treated children. Declines in parasitaemia were monoexponential with an estimated elimination half-time of 1 h. Elimination half-times were similar for both treatments. In children aged 2 years and under who were anaemic at presentation, the mean anaemia recovery time was 12.1 days (95 % CI 10.6–13.6, n = 127), which was similar for both treatments. Relatively asymptomatic LAA occurred in 11 children (4.4 %) aged 2 years and under, the recovery from which was uneventful.ConclusionThis study showed that AA and AL are efficacious treatments for uncomplicated falciparum malaria in Nigerian children aged 2 years and under, and that AA clears parasitaemia and fever significantly faster than AL in children older than 2 years. Both treatments may cause a relatively asymptomatic LAA with uneventful recovery in a small proportion of children aged 2 years and under.Trials registrationPan African Clinical Trial Registry PACTR201508001188143, 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015 http://www.pactr.org.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-016-0165-2) contains supplementary material, which is available to authorized users.

Urinary deoxynivalenol (DON) and zearalenone (ZEA) as biomarkers of DON and ZEA exposure of pigs.

Four diets contaminated with 1.1 to 5.0 mg/kg deoxynivalenol (DON) and 0.4 to 2.4 mg/kg zearalenone (ZEA) were fed to four groups of six growing Large White pigs. Urine samples were collected after 3 to 4 days and again after 6 to 7 days on the diets. On each sampling day, half of the animals were sampled in the morning, after an 8-h fast, and the other half were sampled in the afternoon, after 7 h of ad libitum access to feed. The urinary concentrations of DON, DON-glucuronide, DON-3-sulphate, de-epoxy-DON, as well as of ZEA, ZEA-14-glucuronide, α-zearalenol and α-zearalenol-14-glucuronide, analysed using LC-MS/MS, were used to calculate urinary DON and ZEA equivalent concentrations (DONe and ZEAe). The urinary concentration of DONe (P < 0.001), but not of ZEAe (P = 0.31), was lower in the fasted than that in the fed animals. The urinary DONe/creatinine and ZEAe/creatinine ratios were highly correlated with DON and ZEA intake per kg body weight the day preceding sampling (r = 0.76 and 0.77; P < 0.001). The correlations between DON intake during the 7 h preceding urine sampling in the afternoon and urinary DONe/creatinine ratio (r = 0.88) as well as between mean ZEA intake during 3 days preceding urine sampling and urinary ZEAe/creatinine ratio (r = 0.84) were even higher, reflecting the plasma elimination half-time of several hours for DON and of more than 3 days for ZEA. ZEAe analysed in enzymatically hydrolysed urine using an ELISA kit was highly correlated with the LC-MS/MS data (r = 0.94). The urinary DONe and ZEAe to creatinine ratios, analysed in pooled urine samples of several pigs fed the same diet, can be used to estimate their exposure to DON and ZEA.

Long Circulation Red‐Blood‐Cell‐Mimetic Nanoparticles with Peptide‐Enhanced Tumor Penetration for Simultaneously Inhibiting Growth and Lung Metastasis of Breast Cancer

Limited blood circulation and poor tumor penetration are two main obstacles hampering the clinical translation of conventional nanosized drug delivery systems (NDDS). Here, red‐blood‐cell (RBC)‐mimetic nanoparticles (NPs) with long circulation and peptide‐enhanced tumor penetration for treating metastatic breast cancer are reported. The RBC‐mimetic NPs are composed of a paclitaxel (PTX)‐loaded polymeric core and a hydrophilic RBC vesicle shell. The RBC‐mimetic NPs display dramatically elongated blood circulation with an elimination half time of 32.8 h, 5.8‐fold higher than that of the parental polymeric NPs (i.e., 5.6 h). Moreover, the experimental results demonstrate that the tumor penetration ability of the RBC‐mimetic NPs can be significantly improved by coadministrating with a tumor‐penetrating peptide iRGD. Antitumor studies using a metastatic 4T1 breast tumor model show that RBC‐mimetic NPs in combination with iRGD significantly inhibit over 90% of the tumor growth and suppress 95% of the lung metastasis, much more efficient than PTX‐loaded polymer NP alone or the combination of polymer NPs and iRGD. The results reveal the importance of both long circulation and tumor penetration of nanosized drugs for efficient cancer therapy, which can provide a new insight for NDDS design.

Sodium dehydroacetate levels in chicken tissues

Sodium dehydroacetate (Na-DHA), which has preservative and antimicrobial effects, is used as food and feed additive. However, there is little information on the Na-DHA levels in foods derived from animals fed Na-DHA. In this study, an HPLC-based method with methanol and 0.02% ammonium acetate (31:69, v/v) as the mobile phase was developed to determine Na-DHA residues in chicken muscle, liver, kidney, and skin fat tissues. Forty-eight yellow-plumage broiler chickens were administered 200mg/kg Na-DHA in their feed for 30d and sacrificed at different time points. In this study, the limit of detection was 0.08mg/kg and the limit of quantification was 0.2mg/kg. The residue concentration of Na-DHA in chicken tissues was <0.7mg/kg. The elimination half-times of Na-DHA were 5.86d for kidney tissues, 6.02d for liver tissues, 8.88d for muscle tissues, and 10.38d for skin fat tissues. The residue levels of Na-DHA were lower than dehydroacetic acid in chicken tissues in our previous work, implying less risk of Na-DHA residue in chicken tissues compared to its acid.

Determination and pharmacokinetic study of four xanthones in rat plasma after oral administration of Gentianella acuta extract by UHPLC–ESI–MS/MS

Ethnopharmacological relevanceGentianella acuta (Michx.) Hulten belonging to the family of Gentianaceae is an annual plant mainly distributed in north of China, Mongolia plateau, Siberia and Far East areas of Russia. The whole herb was used as folk medicine to treat hepatitis, jaundice, headache and fever in Mongolia native medicine. Xanthones are the main active compounds of G. acuta and possess a lot of pharmacological and biological activities Aim of the studyA selective and sensitive UHPLC–MS/MS method was developed and validated for the determination and pharmacokinetic study of swertianolin, norswertianolin, bellidifolin and demethylbellidifolin (DMB) in rat plasma after oral administration of G. acuta extract. Materials and methodsSample preparation involved a liquid–liquid extraction of the analytes with ethyl acetate. Butylparaben was employed as an internal standard. LC separation was achieved on an Agilent SB-C18 RRHD column (1.8μm, 150mm×2.1mm) at 30°C with an isocratic mobile phase consisting of acetonitrile–water (0.1% formic acid) (90:10, v/v). The detection was accomplished by multiple-reaction monitoring (MRM) scanning with electrospray ionization (ESI) source operating in the negative ionization mode. The optimized mass transition ion-pairs (m/z) monitored for swertianolin, norswertianolin, bellidifolin, DMB and I.S. were 435.1/272.0, 420.8/258.9, 273.0/258.0, 258.9/214.9 and 193.0/92.0, respectively. ResultsThe current UHPLC–MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability and was suitable for pharmacokinetic studies of the four xanthones after oral administration of G. acuta extract. The time to reach the maximum plasma concentration (Tmax) was 0.40±0.12h for swertianolin, 0.27±0.07h for norswertianolin, 1.00±0.18h for bellidifolin and 0.94±0.15h for demethylbellidifolin. The elimination half-time (t1/2) of swertianolin, norswertianolin, bellidifolin and DMB, was 19.7±9.64h, 11.3±4.51h, 19.9±8.11h and 24.9±8.19h, respectively. ConclusionThis study described a simple, sensitive and validated UHPLC–MS/MS method for simultaneous determination of four xanthones in rat plasma after oral administration of G. acuta extract, and investigated on their pharmacokinetic studies as well.

Human metabolism and excretion kinetics of aniline after a single oral dose.

Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9% of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1%. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36% of the dose. Overall, these four biomarkers excreted in urine over 48h post-dose represented 62.4-72.1% of the oral aniline dose. Elimination half-times were 3.4-4.3h for N-acetyl-4-aminophenol, 4.1-5.5h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4h and maximum concentrations of the mercapturic acid conjugate after about 6h, whereas concentrations of acetanilide and free aniline peaked after about 1h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen.

Pharmacokinetics of bisphenol A in humans following a single oral administration

BackgroundHuman exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. ObjectiveTo reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. MethodsWe exposed six men and eight women to 100μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. ResultsMean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711nM (390ng/ml) was observed at Tmax of 1.1±0.50h. Unconjugated d6-BPA appeared in serum within 5–20min of dosing with a mean Cmax of 6.5nM (1.5ng/ml) observed at Tmax of 1.3±0.52h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48h in some subjects at concentrations near the LOD (0.001–0.002ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4±2.0h and 6.2±2.6h, respectively. Recovery of total administered d6-BPA in urine was 84–109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h. ConclusionsUsing more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h.

A model of the ocular pharmacokinetics involved in the therapy of neovascular age-related macular degeneration with ranibizumab

BackgroundTo develop a model of the pharmacokinetics of vascular endothelial growth factor (VEGF-A) determined in samples of aqueous humour from patients with neovascular age-related macular degeneration (AMD) treated with ranibizumab...

Effects of recombinant human thyroid stimulating hormone on 131I therapy for the treatment of differentiated thyroid cancer.

The aim of the present study was to compare the advantages and disadvantages of the combined application of recombinant human thyroid stimulating hormone (rhTSH) with thyroid hormone withdrawal (THW) and THW alone prior to 131I therapy for the treatment of differentiated thyroid cancer. Four indicators were compared between the experimental group, who received a combined therapeutic method of rhTSH with THW, and the control group, who received THW therapy alone. With the exception of the elimination half-time of 131I in the blood in the experimental group, which was significantly shorter compared with that in the control group, the other three indicators, including the urinary iodine concentration, the relative 131I uptake ratio of the neck lesions and the one-time cure rate, were not significantly different between the two groups. In addition, the treatment efficacy of 131I therapy exhibited no statistically significant difference between the experimental and control groups. However, in the experimental group, the residence time of 131I in the blood was significantly shorter compared with that in the control group, indicating that the irradiation damage of radioactive iodine exposure to the non-target tissues was lower in the experimental group when compared with the control group. In addition, no evident hypothyroidism was observed in the patients. Thus, the combined application of rhTSH with THW prior to 131I therapy was demonstrated to be superior to the THW therapy alone.