Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics.

Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. This study aimed to investigate the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). Concentrations of atomoxetine and its metabolites were analyzed using high-performance liquid chromatography with tandem mass spectrometry in plasma samples that were collected up to 24 hours after drug intake. For atomoxetine, the CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0-∞ (area under the plasma concentration-time curve from 0 to infinity) and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups (P < 0.001 for all). The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups (P < 0.01 for CYP2C19EM and P < 0.05 for CYP2C19IM groups). The maximum plasma concentration and AUC 0-∞ of 4-hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups (P < 0.001 for CYP2C19EM and P < 0.05 for CYP2C19IM, respectively), whereas the corresponding values for N-desmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups (P < 0.001 for both genotype groups). These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine.

Metabolism of 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether (pyridalyl) in rats after repeated oral administration and a simple physiologically based pharmacokinetic modeling in brown and white adipose tissues.

Male and female Sprague-Dawley rats received repeated oral administration of 14C-2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3- [5-(trifluoromethyl)-2-pyridyloxy]propyl ether (14C-pyridalyl) at 5 mg/kg/day for 14 consecutive days, and 14C excretion, 14C concentration in tissues, and the metabolic fate were determined. Most 14C was excreted into feces. The 14C concentrations in the blood and tissues attained steady-state levels at days 6 to 10, whereas those in white adipose tissues increased until day 14. Tissue 14C concentrations were highest in brown and white adipose tissue (38.37-57.50 ppm) but were 5.60 ppm or less in all the other tissues. Total 14C residues in blood and tissues on the 27th day after the first administration accounted for 2.6 to 3.2% of the total dose. A major fecal metabolite resulted from O-dealkylation. Analysis of metabolites in tissues revealed that the majority of 14C in perirenal adipose tissue and lungs was pyridalyl, accounting for greater than 90 and 60%, respectively, of the total, whereas a major metabolite in whole blood, kidneys, and liver was a dehalogenated metabolite. The experimental data were simulated with simple physiologically based pharmacokinetics using four-compartment models with assumption of lymphatic absorption and membrane permeability in adipose tissues. The different kinetics in brown and white adipose tissues was reasonably predicted in this model, with large distribution volume in adipose tissues and high hepatic clearance in liver. Sex-related difference of pyridalyl concentration in liver was considered to be a result of different unbound fraction times the hepatic intrinsic clearance (f x CL(int)) of 1.8 and 12 l/h for male and female, respectively.

Evaluation of the Pharmacokinetic Interaction Between the Voltage- and Use-Dependent Nav1.7 Channel Blocker Vixotrigine and Carbamazepine in Healthy Volunteers.

Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC0-tau ) and maximum observed concentration (Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.

Metabolism of pyridalyl in rats.

Metabolism of pyridalyl [2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether] was examined in male and female Sprague-Dawley rats. After a single oral administration of [dichlorophenyl-(14)C]pyridalyl at 5 or 500 mg/kg, the (14)C concentration in blood reached maxima at 2 to 10 h and then decreased rapidly with a biological half-life of approximately 11 to 12 h. (14)C concentrations in liver, fat, adrenal gland, and spleen were relatively high at a low dose, reaching 2.3 to 2.7, 1.9 to 2.3, 1.1 to 1.9, and 1.4 ppm, respectively, in these tissues at 2 to 24 h after administration. Although (14)C elimination from fat and hair and skin was relatively slow compared with that from other tissues, the total residue on the 7th day was low, in the range of 1.3 to 2.3% of the dose. The (14)C distribution in tissues with a high dose, as examined by whole-body autoradiography, was similar to that observed for the low dose. Results revealed that more than 88% of the dosed radiocarbon was excreted within 1 day after administration, with cumulative (14)C excretion into urine and feces 7 days after administration of 1.7 to 2.6 and 98.7 to 101.7%, respectively. One urinary and fecal major metabolite (resulting from O-dealkylation) and two minor metabolites were identified by NMR and mass spectrometry. Residual (14)C in fat was extracted, and analysis by thin-layer chromatography showed it to be due to pyridalyl itself. No marked sex-related differences were observed in (14)C elimination, (14)C distribution, and metabolites.

Polybrominated diphenyl ethers (PBDEs) and bioaccumulative hydroxylated PBDE metabolites in young humans from Managua, Nicaragua.

OBJECTIVE: Our aim was to investigate exposure to polybrominated diphenyl ethers (PBDEs) in a young urban population in a developing country, with focus on potentially highly exposed children working informally as scrap scavengers at a large municipal waste disposal site. We also set out to investigate whether hydroxylated metabolites, which not hitherto have been found retained in humans, could be detected. METHODS: We assessed PBDEs in pooled serum samples obtained in 2002 from children 11-15 years of age, working and sometimes also living at the municipal waste disposal site in Managua, and in nonworking urban children. The influence of fish consumption was evaluated in the children and in groups of women 15-44 years of age who differed markedly in their fish consumption. Hydroxylated PBDEs were assessed as their methoxylated derivates. The chemical analyses were performed by gas chromatography/mass spectrometry, using authentic reference substances. RESULTS: The children living and working at the waste disposal site showed very high levels of medium brominated diphenyl ethers. The levels observed in the referent children were comparable to contemporary observations in the United States. The exposure pattern was consistent with dust being the dominating source. The children with the highest PBDE levels also had the highest levels of hydroxylated metabolites. CONCLUSIONS: Unexpectedly, very high levels of PBDEs were found in children from an urban area in a developing country. Also, for the first time, hydroxylated PBDE metabolites were found to bioaccumulate in human serum.

Tissue-specific congener composition of organohalogen and metabolite contaminants in East Greenland polar bears (Ursus maritimus).

Congener patterns of the major organohalogen contaminant classes of PCBs, PBDEs and their metabolites and/or by-products (OH-PCBs, MeSO2-PCBs, OH-PBDEs and MeO-PBDEs) were examined in adipose tissue, liver, brain and blood of East Greenland polar bears (Ursus maritimus). PCB, OH-PCB, MeSO2-PCB and PBDE congener patterns showed significant differences (p

Flame retardants (PBDEs) in marine turtles, dugongs and seafood from Queensland, Australia.

Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in numerous products. These compounds have been found to enter the marine environment where they have the potential to bioaccumulate in biota. Limited information is currently available concerning the levels of PBDEs in Australian marine wildlife. This study presents baseline information on PBDE levels in a variety of marine species from Queensland, Australia and considers the influence of species-specific factors on contaminant levels and tissue distribution in marine turtles. Overall, the PBDE levels measured in this study are relatively low compared to marine biota from the northern hemisphere, indicating low level input into the marine system of Queensland. This is in general agreement with global estimates which suggest low PBDE usage in Australia. Previous studies, however, have found relatively high PBDE levels in Australian human milk and sera. This discrepancy in contamination trends between terrestrial and marine biota suggests that future transport of PBDEs may occur to the marine system in Australia.

Isolation and recovery of selected polybrominated diphenyl ethers from human serum and sheep serum: coupling reversed-phase solid-phase disk extraction and liquid-liquid extraction techniques with a capillary gas chromatographic electron capture negative ion mass spectrometric determinative technique.

Polybrominated diphenyl ethers (PBDEs) are isolated and recovered with acceptable percent recoveries from human serum via liquid-liquid extraction and column chromatographic cleanup and fractionation with quantitation using capillary gas chromatography-mass spectrometry with electron capture negative ion and selected ion monitoring. PBDEs are found in unspiked serum. An alternative sample preparation approach is developed using sheep serum that utilizes a formic acid pre-treatment followed by reversed-phase solid-phase disk extraction and normal-phase solid-phase cleanup using acidified silica gel that yields>50% recoveries. When these percent recoveries are combined with a minimized phase ratio for human serum and very low instrument detection limits, method detection limits below 500 parts-per-trillion are realized.

Single Administration of HBK-15-a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist-Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone.

Studies suggest that the blockade of 5-HT1A, 5-HT7, and 5-HT3 receptor may increase the speed of antidepressant response. 1-[(2,6-Dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15), dual 5-HT1A and 5-HT7 antagonists, showed significant antidepressant- and anxiolytic-like properties in our previous tests in rodents. In this study, we aimed to investigate their antidepressant potential using mouse model of corticosterone-induced depression. We chose sucrose preference test, forced swim test, and elevated plus maze to determine anhedonic-, antidepressant-, and anxiolytic-like activities. We also evaluated the influence of the active compound on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus. Moreover, for both compounds, we performed biofunctional (5-HT3 receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT3 receptor antagonists. HBK-14 (2.5 mg/kg) and HBK-15 (1.25 mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration permeated the blood-brain barrier with brain/plasma ratio lower than 1. The bioavailability of studied compounds after i.p. administration was 15% for HBK-14 and 54% for HBK-15. Chronic administration of HBK-15 (1.25 mg/kg) and fluoxetine (10 mg/kg) protected corticosterone-treated mice from anhedonic-, depressive-, and anxiety-like behaviors, as well as decreases in BDNF and NGF levels in the hippocampus. HBK-14 (2.5 mg/kg) counteracted anxiety-like behaviors in corticosterone-treated mice. Single administration of HBK-15 (1.25 mg/kg) and ketamine (1 mg/kg) reversed depression-like behavior and regulated decreased BDNF level in the hippocampus in corticosterone-treated mice. Our results suggest that simultaneous blockade of serotonergic 5-HT1A, 5-HT7, and 5-HT3 receptors might accelerate antidepressant response.

Polybrominated diphenyl ether levels in the blood of pregnant women living in an agricultural community in California.

BACKGROUND: Recent studies have raised concerns about polybrominated diphenyl ether (PBDE) flame retardant exposures to pregnant women and women of child-bearing age in the United States. Few studies have measured PBDEs in immigrant populations. OBJECTIVES: Our goal was to characterize levels of seven PBDE congeners, polychlorinated biphenyl (PCB)-153, and polybrominated biphenyl (PBB)-153 in plasma from 24 pregnant women of Mexican descent living in an agricultural community in California. RESULTS: The median concentration of the sum of the PBDE congeners was 21 ng/g lipid and ranged from 5.3 to 320 ng/g lipid. Consistent with other studies, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was found at the highest concentration (median = 11 ng/g lipid; range, 2.5-205) followed by 2,2',4,4',5-pentabromobiphenyl (BDE-99) (median = 2.9 ng/g lipid; range, 0.5-54), 2,2',4,4',5-pentaBDE (BDE-100) (median = 1.8 ng/g lipid; range, 0.6-44), and 2,2',4,4',5,5'-hexaBDE (BDE-153) (median = 1.5 ng/g lipid; range, 0.4-35). Levels of PCB-153 (median= 4.4 ng/g lipid; range, < 2-75) were lower than U.S. averages and uncorrelated with PBDE levels, suggesting different exposure routes. CONCLUSIONS: The overall levels of PBDEs found were lower than levels observed in other U.S. populations, although still higher than those observed previously in Europe or Japan. The upper range of exposure is similar to what has been reported in other U.S. populations. PBDEs have been associated with adverse developmental effects in animals. Future studies are needed to determine the sources and pathways of PBDE exposures and whether these exposures have adverse effects on human health.

Determinants of prenatal exposure to polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in an urban population.

BACKGROUND: Recent studies have reported blood levels of polybrominated diphenyl ethers (PBDEs) in the U.S. population. Information about neonatal levels and about the relationship to polychlorinated biphenyls (PCBs) exposures is limited. OBJECTIVES: The objective was to characterize levels and determinants of fetal exposure to PBDEs and PCBs among newborns from Baltimore, Maryland. METHODS: We analyzed umbilical cord blood for eight PBDEs and 35 PCBs from infants delivered at the Johns Hopkins Hospital. Maternal and infant characteristics were abstracted from medical records. RESULTS: Ninety-four percent of cord serum samples had quantifiable levels of at least one PBDE congener, and > 99% had at least one detectable PCB congener. PBDE concentrations in cord blood were similar to those reported in other studies from North America. Strong correlations were observed within but not across PCB and PBDE classes. Multivariate models showed that many factors independently predicted exposure to BDE-47, BDE-100, and BDE-153 and CB-118, CB-138/158, CB-153, and CB-180. Generally, infants of Asian mothers had lower PBDE and PCB levels, and infants of smokers had higher levels. Increased maternal body mass index was associated with lower levels of PCBs but not PBDEs. Levels of PCBs but not PBDEs were lower in births from married and multiparous mothers. Increased maternal age was associated with higher PCB levels but lower PBDE levels. CONCLUSIONS: Although many of the factors we investigated were independent predictors of both PBDE and PCB levels, in some cases the direction of associations was different. More research is needed to better understand the sources and pathways of PBDE exposure.

Plasma concentrations of selected organobromine compounds and polychlorinated biphenyls in postmenopausal women of Québec, Canada.

BACKGROUND: Brominated flame retardants, especially polybrominated diphenyl ethers (PBDEs), have been widely used in North America, but little is known about the level of exposure of human populations to these compounds. OBJECTIVES: We set out to assess the internal exposure of postmenopausal Canadian women to selected organobromine compounds and to investigate factors associated with this exposure. METHODS: We measured concentrations of four PBDEs, one polybrominated biphenyl, and for comparative purposes, 41 polychlorinated biphenyl (PCB) congeners in plasma samples from 110 healthy postmenopausal women who were recruited at a mammography clinic in 2003-2004. RESULTS: PBDE-47 was the major PBDE congener, with a mean (geometric) concentration of 8.1 ng/g lipids and extreme values reaching 1,780 ng/g. By comparison, the mean concentration of the major PCB congener (PCB-153) was 41.7 ng/g and the highest value was 177 ng/g. PBDEs 47, 99, and 100 were strongly intercorrelated, but weaker correlations were noted with PBDE-153. As the sum of PBDEs (summation operatorPBDEs) increased, the relative contribution of PBDE-47 to the summation operatorPBDEs increased, whereas that of PBDE-153 decreased. PBDE-153 was the only brominated compound correlated to PCB-153. PBDE levels were not linked to any sociodemographic, anthropometric, reproductive, or lifestyle variables documented in the present study. Age and body mass index gain since the age of 18 years were significant predictors of PCB-153 plasma levels. CONCLUSION: Our results suggest that exposure to PBDE-47 likely occurs through direct contact with the penta-PBDE formulation, whereas exposure to PBDE-153 may originate in part from the food chain.

A simple and fast method for the simultaneous determination of polychlorinated biphenyls and polybrominated diphenyl ethers in small volumes of human serum.

A fast extraction and clean-up method for the simultaneous determination of PCBs and PBDEs has been developed. The procedure consisted of a solid-phase extraction (SPE) of the analytes on an Oasis HLB cartridge and the subsequent on-line fat elimination by directly dropping the eluate from the SPE cartridge onto a second cartridge containing layers of activated neutral silica gel and sulphuric acid modified silica gel. Detection limits using a gas chromatography coupled with an ion trap detector in the tandem mass spectrometry mode were from 0.03 to 0.3 pg/microL for PCBs and from 0.07 to 1.3 pg/microL for PBDEs. Repeatability (lower than 11%) and reproducibility (lower than 17%), expressed as relative standard deviation (RSD, n=4), were satisfactory. The feasibility of the method developed for the determination of the target compounds was evaluated by participation in several rounds of interlaboratory exercises involving human serum with a wide range of PBDE and PCB concentrations. The method has been applied to the evaluation of PBDEs and PCBs in human serum samples of up to 1 mL.

Exposure to polybrominated diphenyl ethers among workers at an electronic waste dismantling region in Guangdong, China.

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants. The aim of the present study was to evaluate the PBDE serum levels in residents from an electronic waste dismantling region, residents living within 50 km of the dismantling region, and a referent group with no occupational PBDE exposure. Fourteen PBDE congeners including BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, BDE-183, BDE-196, BDE-197, BDE-203, BDE-206, BDE-207, BDE-208 and BDE-209 were quantified in these three groups by gas chromatography-negative chemical ionization (NCI) mass spectrometry in selected ion monitoring (SIM) mode. We found that the levels of all PBDE congeners in serum of residents from electronic waste dismantling region were significantly higher than those in the two other groups. The referents showed the lowest PBDE levels. Concentrations of congeners with a high number of bromine substituents, i.e., hepta- to decaBDEs in occupational exposure workers were 11-20 times higher than those in the referent group. BDE-209 was the dominant congener. The highest concentration of BDE-209 was observed among the electronic waste dismantling workers, and it was 3436 ng g(-1) lipid weight (ng g(-1) l.w.), which is the highest concentration of BDE-209 in humans worldwide. Some higher brominated PBDE congeners such as BDE-197, BDE-207 and BDE-208 also showed elevated concentrations in dismantling workers. This study confirms that BDE-209 is released to the environment and can bioaccumulate in the blood of electronic waste dismantling workers, and extensive occupational exposure to PBDEs leads to elevated concentrations of all PBDE congeners in serum.

Integrated Exposure Assessment Survey (INES) exposure to persistent and bioaccumulative chemicals in Bavaria, Germany.

The Integrated Exposure Assessment Survey (INES) was started in the year 2005. Altogether 50 healthy adults living in Bavaria, Germany, were included into the study. Monitoring was conducted in accordance with relevant routes of human exposure (inhalation, ingestion) and integrated different pathways (indoor air, food, house dust). This approach consisted of a combination of external measurements of contaminants with the determination of these substances or their metabolites in body fluids. The target substances were phthalates, perfluorinated compounds (PFC), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), and polybrominated diphenylethers (PBDEs). This paper gives a brief description of the objectives and the concept of INES as well as methods of sampling and analyses of target compounds. Some preliminary results of biomonitoring data for PFC and phthalates as well as of the dietary intake of DEHP will be discussed.

Organohalogen contamination in breeding glaucous gulls from the Norwegian Arctic: associations with basal metabolism and circulating thyroid hormones.

Exposure to organohalogens in endotherms has been suggested to impose chemically induced stress by affecting functions related to maintenance energy requirements. Effects on basal metabolic rate (BMR) have been suggested to be, in part, mediated through interactions with the thyroid hormones (THs). We investigated the relationships between plasma concentrations of major organochlorines, PBDEs, hydroxylated (OH)- and methoxylated (MeO)-PBDEs and OH-PCBs, circulating TH levels and BMR in breeding glaucous gulls (Larus hyperboreus) from the Norwegian Arctic. Negative associations were found between BMR and concentrations of sigma PCB, Sigma DDT and particularly Sigma chlordane, which combined made up 91% of the total contaminant burden. Levels of THs (thyroxine and triiodothyronine) were not associated significantly with variation of BMR or concentrations of any of the compounds determined. The present study suggests that BMR may be altered in glaucous gulls exposed to high loadings of persistent contaminants in the Norwegian Arctic environment.

Accumulation, tissue-specific distribution and debromination of decabromodiphenyl ether (BDE 209) in European starlings (Sturnus vulgaris).

In this study we investigated the accumulation, tissue-specific distribution and possible debromination of BDE 209 in a terrestrial songbird species, the European starling, using silastic implants as a method of exposure. BDE 209 accumulated in the blood of the exposed starlings to a mean peak concentration of 16+/-4.1 ng/ml on day 10. After this peak, there was a decline to 3.3+/-0.4 ng/ml blood at the end of the exposure period of 76 days, which suggests elimination of BDE 209. In the exposed group, the muscle concentrations (461 ng/g lipid weight [lw], 430 ng/g lw) were about twofold those in liver (269 ng/g lw, 237 ng/g lw). In addition to BDE 209, other PBDE congeners, particularly octa- and nonaBDEs, were also present in the muscle and liver, suggesting bioformation from BDE 209. To our knowledge, these results are the first indications for the debromination of BDE 209 in birds.

Polybrominated diphenyl ethers in blood from Korean incinerator workers and general population.

This study was conducted to examine PBDE exposure in Koreans, with a special focus on incinerator workers due to their potential for occupational exposure to PBDEs. A total of 92 blood samples from 30 incinerator workers, 51 nearby residents and 11 controls were analyzed. The mean total PBDE concentration calculated from the 13 most concentrated congeners for all samples was 16.84+/-7.48 ng/g lipid, which was somewhat higher concentration than in other countries except North America and Canada. The PBDE levels and congener profiles detected in incinerator workers were not distinctly different from those found in the general population. In all groups tested, BDE-47 was dominant (mean contribution=32.5%) followed by BDE-153 (23.6%) and relatively high portions of BDE-183 (16.5%) were found. No strong trend was observed between PBDE levels and a number of key biological factors examined in this study, however, weak correlations were observed in PBDE levels measured against dietary habits, particularly in fish consumption frequency and gender. Overall, our data suggest that the occupational exposure of incinerator workers to PBDEs can be considered minor, while other lifestyle factors can have a greater contribution to PBDE exposure.

Plasma PBDE and thyroxine levels in rats exposed to Bromkal or BDE-47.

In experimental models, polybrominated diphenyl ethers (PBDEs), a group of brominated flame retardants, have caused effects in a number of biological end-points, including neurobehavioural effects, disturbances in thyroid and steroid hormone homeostasis, and other steroid-related effects. Almost exclusively, only external dose metrics (dose per body weight basis) have been studied in connection to the observed effects. In this study we report on new analyses of plasma PBDE levels in surplus samples from earlier studies on thyroid hormones (TH) in exposed rodents. Female, 7-week old Sprague-Dawley rats were given either Bromkal 70-5 DE (Study I; 18 or 36 mg/kg bw/day) or BDE-47 (Study II; 1, 6 or 18 mg/kg bw/day) daily by gavage for two weeks. At an external dose of 18 mg/kg bw/day significant TH effects (decreased plasma free thyroxin levels) were observed in both studies, corresponding to an internal (plasma) dose of 463 microg sumPBDE/g lipid (Study I) or 421 microg BDE-47/g lipid (Study II). If we compare the contribution of different BDE congeners to the total BDE level in rat plasma after Bromkal exposure (Study II), and in the Bromkal mixture itself, the most important congener in the Bromkal mixture were also found in plasma. However, the relative concentration of BDE-99 was lower, and that of BDE-153 was higher, than that of the mixture, indicating selectivity in uptake, metabolism and/or excretion of the individual BDE congeners. Explicitly, the possible in vivo conversion of BDE-99 to BDE-47, and of BDE-154 to BDE-153 could not be excluded. The internal dose in the present rat study could be compared to reported human serum doses of PBDE. Human serum/blood levels have a wide range, from 3 to 6 ng sumPBDE/g lipid in background samples from Europe, about 10 times higher in US sample, and up to 100 times higher (300-600 ng/g lipid) in upper-end levels in collected samples from USA. As a consequence, the margin between effects levels in the rat and exposure levels in man varies widely, with a quotient roughly from 1000 to 100,000. Generally, it could be expected that this margin is lower than if external dose metrics would be used. An even lower margin could be expected as recent studies have shown effects in offspring at lower doses than those giving effects in our studies. Lastly, it should be noted that humans are already exposed to a mixture of chemicals in daily life, a fact that complicates this kind of comparison.

Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects.

PURPOSE: GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study. PROCEDURES: [18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 µg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded. RESULTS: PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [18F]GSK2647544 present after 120 min. CONCLUSIONS: The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity. TRIAL REGISTRATION: Clintrials.gov: NCT01924858.