Metabolites In Adults Research Articles

Pea hull fiber supplementation does not modulate uremic metabolites in adults receiving hemodialysis: a randomized, double-blind, controlled trial.

Fiber is a potential therapeutic to suppress microbiota-generated uremic molecules. This study aimed to determine if fiber supplementation decreased serum levels of uremic molecules through the modulation of gut microbiota in adults undergoing hemodialysis. A randomized, double-blinded, controlled crossover study was conducted. Following a 1-week baseline, participants consumed muffins with added pea hull fiber (PHF) (15 g/d) and control muffins daily, each for 4 weeks, separated by a 4-week washout. Blood and stool samples were collected per period. Serum p-cresyl sulfate (PCS), indoxyl sulfate (IS), phenylacetylglutamine (PAG), and trimethylamine N-oxide (TMAO) were quantified by LC-MS/MS, and fecal microbiota profiled by 16S rRNA gene amplicon sequencing and specific taxa of interest by qPCR. QIIME 2 sample-classifier was used to discover unique microbiota profiles due to the consumption of PHF. Intake of PHF contributed an additional 9 g/d of dietary fiber to the subjects' diet due to compliance. No significant changes from baseline were observed in serum PCS, IS, PAG, or TMAO, or for the relative quantification of Akkermansia muciniphila, Faecalibacterium prausnitzii, Bifidobacterium, or Roseburia, taxa considered health-enhancing. Dietary protein intake and IS (r = -0.5, p = 0.05) and slow transit stool form and PCS (r = 0.7, p < 0.01) were significantly correlated at baseline. PHF and control periods were not differentiated; however, using machine learning, taxa most distinguishing the microbiota composition during the PHF periods compared to usual diet alone were enriched Gemmiger, Collinsella, and depleted Lactobacillus, Ruminococcus, Coprococcus, and Mogibacteriaceae. PHF supplementation did not mitigate serum levels of targeted microbial-generated uremic molecules. Given the high cellulose content, which may be resistant to fermentation, PHF may not exert sufficient effects on microbiota composition to modulate its activity at the dose consumed.

The Association between Circulating 25-Hydroxyvitamin D and Carotid Intima-Media Thickness Is Mediated by Gut Microbiota and Fecal and Serum Metabolites in Adults.

Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults. This 9-year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9-year cIMT changes at the common carotid artery (hΔCCA-cIMT) (p-trend<0.001). Multivariable-adjusted OR (95%CI) of hΔCCA-cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73-1.04) and 0.68 (0.57-0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA-cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA-cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p<0.05), respectively. These findings show a beneficial association between plasma 25(OH)D and the CCA-cIMT progression. The identified multi-omics biomarkers provide novel mechanistic insights for the epidemiological association.

Population Pharmacokinetic Analysis of the RNAi Therapeutic Givosiran in Patients with Acute Hepatic Porphyria.

Givosiran, approved for the treatment of acute hepatic porphyria (AHP), is the first subcutaneously administered RNAi therapeutic. This analysis was undertaken to describe the plasma pharmacokinetics (PK) of givosiran and its active metabolite, AS(N-1)3' givosiran, and to identify factors that contribute to intersubject PK variability. A population PK model was developed using data from givosiran clinical trials that enrolled patients with AHP or who were asymptomatic chronic high excreters (CHEs) of toxic heme intermediates. Givosiran and AS(N-1)3' givosiran PK were modeled simultaneously using non-linear mixed-effects modeling. Plasma PK of givosiran was best described by a two-compartment model. Givosiran absorption after subcutaneous administration and conversion of givosiran to AS(N-1)3' givosiran were incorporated as first-order processes. Hepatic clearance was the major route of elimination from the central compartment, with renal clearance accounting for < 20% of the total clearance. Body weight, East Asian ethnicity, and renal impairment were significant covariates in the model; however, none of the covariates evaluated resulted in clinically meaningful differences in plasma exposures of givosiran and AS(N-1)3' givosiran. The model adequately described observed concentrations and variability across a wide range of dose levels. Model-derived simulations showed similar exposures for givosiran and its active metabolite in adults and adolescents. The PK of givosiran and its active metabolite were not significantly affected by demographic or clinical parameters that would require adjustment from the approved body weight-based dose of givosiran 2.5 mg/kg once monthly.

Effects of Lanthanum Carbonate on Whole-Body Calcium Balance, Vascular Function, and Mineral Metabolites in Adults With CKD 3b-4 and Normophosphatemia

Effects of Lanthanum Carbonate on Whole-Body Calcium Balance, Vascular Function, and Mineral Metabolites in Adults With CKD 3b-4 and Normophosphatemia

Impact of wheat aleurone on biomarkers of cardiovascular disease, gut microbiota and metabolites in adults with high body mass index: a double-blind, placebo-controlled, randomized clinical trial

PurposeAleurone is a cereal bran fraction containing a variety of beneficial nutrients including polyphenols, fibers, minerals and vitamins. Animal and human studies support the beneficial role of aleurone consumption in reducing cardiovascular disease (CVD) risk. Gut microbiota fiber fermentation, polyphenol metabolism and betaine/choline metabolism may in part contribute to the physiological effects of aleurone. As primary objective, this study evaluated whether wheat aleurone supplemented foods could modify plasma homocysteine. Secondary objectives included changes in CVD biomarkers, fecal microbiota composition and plasma/urine metabolite profiles.MethodsA parallel double-blind, placebo-controlled and randomized trial was carried out in two groups of obese/overweight subjects, matched for age, BMI and gender, consuming foods supplemented with either aleurone (27 g/day) (AL, n = 34) or cellulose (placebo treatment, PL, n = 33) for 4 weeks.ResultsNo significant changes in plasma homocysteine or other clinical markers were observed with either treatment. Dietary fiber intake increased after AL and PL, animal protein intake increased after PL treatment. We observed a significant increase in fecal Bifidobacterium spp with AL and Lactobacillus spp with both AL and PL, but overall fecal microbiota community structure changed little according to 16S rRNA metataxonomics. Metabolomics implicated microbial metabolism of aleurone polyphenols and revealed distinctive biomarkers of AL treatment, including alkylresorcinol, cinnamic, benzoic and ferulic acids, folic acid, fatty acids, benzoxazinoid and roasted aroma related metabolites. Correlation analysis highlighted bacterial genera potentially linked to urinary compounds derived from aleurone metabolism and clinical parameters.ConclusionsAleurone has potential to modulate the gut microbial metabolic output and increase fecal bifidobacterial abundance. However, in this study, aleurone did not impact on plasma homocysteine or other CVD biomarkers.Trial RegistrationThe study was registered at ClinicalTrials.gov (NCT02067026) on the 17th February 2014.

Physical Activity and Stool Metabolite Relationships Among Adults at High Risk for Colorectal Cancer

Adenomatous polyps are associated with an increased risk of developing colorectal cancer. Physical activity (PA) and spending less time sedentary may reduce risk of polyp recurrence and cancer incidence. This study examined associations between PA, sedentary time, and stool metabolites in adults at high risk for developing colorectal cancer. Participants were ≥18 years old with ≥1 adenomatous polyps removed in the previous 3 years. PA and sedentary time were assessed using an activPAL™ accelerometer. Stool samples were analyzed for short-chain fatty acids, and primary/secondary bile acid metabolites by mass spectrometry. Linear regression models examined associations between PA, sedentary time, and stool parameters, with dietary fiber as a covariate. Participants (N = 21) were 59 (9) years old and had a body mass index of 28.1 (3.35 kg/m2). Light-intensity PA was associated with butyrate (β = 1.88; 95% confidence interval [CI], 0.477 to 3.291) and propionate (β = 1.79; 95% CI, 0.862 to 2.724). Moderate to vigorous PA was associated with deoxycholic acid (β = -6.13; 95% CI, -12.14 to -0.11) and ursodeoxycholic acid (β = -0.45; 95% CI, -0.80 to -0.12) abundance. Both light and moderate to vigorous PA were associated with gut microbial metabolite production. These findings suggest the importance of examining PA intensity alongside stool metabolites for colorectal cancer prevention.

Alterations of Brain Metabolites in Adults With HIV: A Systematic Meta-analysis of Magnetic Resonance Spectroscopy Studies.

A meta-analysis of proton magnetic resonance spectroscopy studies to investigate alterations in brain metabolites in people with HIV (PWH), the relationship between metabolite alterations and combination antiretroviral therapy (cART), and the relationship between metabolite alterations and cognitive impairment. The PubMed database was searched for studies published from 1997 to 2020. Twenty-seven studies were identified, which included 1255 PWH and 633 controls. Four metabolites (N-acetyl aspartate [NAA], myo-inositol [mI], choline [Cho], and glutamatergic metabolites [Glx]) from 5 brain regions (basal ganglia [BG], frontal gray and white matter [FGM and FWM], and parietal gray and white matter [PGM and PWM]) were pooled separately using random-effects meta-analysis. During early HIV infection, metabolite alterations were largely limited to the BG, including Cho elevation, a marker of inflammation. cART led to global mI and Cho normalization (i.e., less elevations), but improvement in NAA was negligible. In chronic PWH on cART, there were consistent NAA reductions across brain regions, along with Cho and mI elevations in the FWM and BG, and Glx elevations in the FWM. Cognitive impairment was associated with NAA reduction and to a lesser degree mI elevation. The BG are the primary region affected during early infection. cART is successful in partially controlling neuroinflammation (global mI and Cho normalization). However, neuronal dysfunction (NAA reductions) and neuroinflammation (mI and Cho elevations) persist and contribute to cognitive impairment in chronic PWH. Novel compounds targeting NAA signal pathways, along with better neuroinflammation control, may help to reduce cognitive impairment in PWH.

Short-term variability in levels of urinary phosphate flame retardant metabolites in adults and children from an e-waste recycling site

In the present study, urine samples (n = 258) were collected from adults (n = 42) and children (n = 22) in an electronic waste (e-waste) recycling site. The concentrations and compositions of six di-esters, or the metabolites of phosphate flame retardants (PFRs), were measured at different time points on consecutive days. Bis(2-chloroethyl) phosphate (BCEP), dibutyl phosphate (DBP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP) were detected in more than 50% of urine samples. The median concentrations of BCEP, DBP, BDCIPP, and DPHP were 2.43–4.80, 0.09–2.65, 0.46–0.89, and 0.66–1.83 ng/mL in adult urine samples, respectively. For children, the median concentrations of BCEP, DBP, BDCIPP, and DPHP were 1.23, 0.08, 0.06, and 0.29 ng/mL in morning urine samples, and 1.86, 0.12, 0.14, and 0.27 ng/mL in nightfall urine samples, respectively. Nightfall urine had generally higher levels of di-esters than those in morning urine for both adults and children (p < 0.05). Children had significantly lower concentrations of di-esters than adults, indicating the occupational exposure risks of PFRs for adults. Significant correlations were observed in levels of BDCIPP (3 out of 6 groups of samples) and DPHP (2 out of 6 groups of samples) in couples (p<0.05). Significant correlations between parents and boys were only observed in BCEP levels in nightfall urine samples, and in DBP levels in morning urine samples (p<0.05). The results suggest that di-ester concentrations in e-waste recycling workers are highly variable depending on the time that samples are collected, which could further influence the estimation of human exposure to PFRs.

One-carbon metabolism nutrient intake and the association between body mass index and urinary arsenic metabolites in adults in the Chihuahua cohort

BackgroundExposure to inorganic arsenic (iAs) via drinking water is a serious global health threat. Various factors influence susceptibility to iAs-associated health outcomes, including differences in iAs metabolism. Previous studies have shown that obesity is associated with iAs metabolism. It has been hypothesized that this association can be explained by confounding from nutritional factors involved in one-carbon metabolism, such as folate or other B vitamins, whose intake may differ across BMI categories and is known be associated with iAs metabolism. However, no studies have explored whether this association is confounded by nutritional factors. MethodsWe investigated the relationship between body mass index (BMI) and the distribution of urinary arsenic species in a cross-sectional cohort of 1166 adults living in Chihuahua, Mexico from 2008 to 2013. Nutrient intake related to one-carbon metabolism, including folate, vitamin B2, and vitamin B12, was assessed using a food frequency questionnaire developed for Mexican populations. Multivariable linear regression was used to estimate the association between BMI and the distribution of urinary arsenic metabolites. Effect modification by drinking water iAs level and sex was also examined. ResultsAfter adjusting for potential confounders, including age, educational attainment, smoking, alcohol consumption, seafood consumption, water iAs, and sex, BMI was negatively associated with the proportion of urinary inorganic arsenic (%U-iAs) and urinary monomethylated arsenic (%U-MMAs) and positively associated with urinary dimethylated arsenic (%U-DMAs). This relationship was not influenced by additional adjustment for folate, vitamin B2, or vitamin B12 intake. Additionally, there was significant effect modification by both drinking water iAs level and sex. ConclusionsThis study provides further evidence for an association between BMI and arsenic metabolism. However, contrary to previous hypotheses, these results suggest that this association is not confounded by the intake of micronutrients involved in one-carbon metabolism.

Concentrations of Purine Metabolites Are Elevated in Fluids from Adults and Infants and in Livers from Mice Fed Diets Depleted of Bovine Milk Exosomes and their RNA Cargos

Humans and mice absorb bovine milk exosomes and their RNA cargos. The objectives of this study were to determine whether milk exosome- and RNA-depleted (ERD) and exosome- and RNA-sufficient (ERS) diets alter the concentrations of purine metabolites in mouse livers, and to determine whether diets depleted of bovine milk alter the plasma concentration and urine excretion of purine metabolites in adults and infants, respectively. C57BL/6 mice were fed ERD (providing 2% of the microRNA cargos compared with ERS) and ERS diets starting at age 3 wk; livers were collected at age 7 wk. Plasma and 24-h urine samples were collected from healthy adults who consumed (DCs) or avoided (DAs) dairy products. Spot urine samples were collected from healthy infants fed human milk (HM), milk formula (MF), or soy formula (SF) at age 3 mo. Purine metabolites were analyzed in liver, plasma, and urine; mRNAs and microRNAs were analyzed in the livers of female mice. We found that 9 hepatic purine metabolites in ERD-fed mice were 1.76±0.43 times the concentrations in ERS-fed mice (P<0.05). Plasma concentrations and urine excretion of purine metabolites in DAs was ≤1.62±0.45 times the concentrations in DCs (P<0.05). The excretion of 13 purine metabolites in urine from SF infants was ≤175±39 times the excretion in HM and MF infants (P<0.05). mRNA expression of 5'-nucleotidase, cytosolic IIIB, and adenosine deaminase in mice fed ERD was 0.64±0.52 and 0.60±0.28 times the expression in mice fed ERS, respectively. Diets depleted of bovine-milk exosomes and RNA cargos caused increases in hepatic purine metabolites in mice, and in plasma and urine from human adults and infants, compared with exosome-sufficient controls. These findings are important, because purines play a role in intermediary metabolism and cell signaling.

Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine.

Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5mg (≥50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials.

The Association of Dietary l-Arginine Intake and Serum Nitric Oxide Metabolites in Adults: A Population-Based Study.

This study was conducted to investigate whether regular dietary intake of l-arginine is associated with serum nitrate + nitrite (NOx). In this cross-sectional study, 2771 men and women, who had participated in the third examination of the Tehran Lipid and Glucose Study (2006–2008), were recruited. Demographics, anthropometrics and biochemical variables were evaluated. Dietary data were collected using a validated 168-food item semi-quantitative food frequency questionnaire and dietary intake of l-arginine was calculated. To determine any association between dietary l-arginine and serum NOx, linear regression models with adjustment for potential confounders were used. Mean age of participants (39.2% men) was 45.9 ± 15.9 years. After adjustment for all potential confounding variables, a significant positive association was observed between l-arginine intake and serum NOx concentrations in the fourth quartile of l-arginine (β = 6.63, 95% CI = 4.14, 9.12, p for trend = 0.001), an association stronger in women. Further analysis, stratified by age, body mass index and hypertension status categories, showed a greater association in middle-aged and older adults (β = 9.12, 95% CI = 3.99, 13.6 and β = 12.1, 95% CI = 6.48, 17.7, respectively). l-arginine intakes were also strongly associated with serum NOx levels in overweight and obese subjects in the upper quartile (β = 10.7, 95% CI = 5.43, 16.0 and β = 11.0, 95% CI = 4.29, 17.5); a greater association was also observed between l-arginine intakes and serum NOx in non-hypertensive (HTN) compared to HTN subjects (β = 2.65, 95% CI = 2.1–3.2 vs. β = 1.25, 95% CI = −1.64–4.15). Dietary l-arginine intakes were associated to serum NOx and this association may be affected by sex, age, body mass index, and hypertension status.

(1)H-MRS metabolites in adults with Down syndrome: Effects of dementia.

To determine if proton magnetic resonance spectroscopy (1H-MRS) detect differences in dementia status in adults with Down syndrome (DS), we used 1H-MRS to measure neuronal and glial metabolites in the posterior cingulate cortex in 22 adults with DS and in 15 age- and gender-matched healthy controls. We evaluated associations between 1H-MRS results and cognition among DS participants. Neuronal biomarkers, including N-acetylaspartate (NAA) and glutamate-glutamine complex (Glx), were significantly lower in DS patients with Alzheimer's should probably be changed to Alzheimer (without ' or s) through ms as per the new naming standard disease (DSAD) when compared to non-demented DS (DS) and healthy controls (CTL). Neuronal biomarkers therefore appear to reflect dementia status in DS. In contrast, all DS participants had significantly higher myo-inositol (MI), a putative glial biomarker, compared to CTL. Our data indicate that there may be an overall higher glial inflammatory component in DS compared to CTL prior to and possibly independent of developing dementia. When computing the NAA to MI ratio, we found that presence or absence of dementia could be distinguished in DS. NAA, Glx, and NAA/MI in all DS participants were correlated with scores from the Brief Praxis Test and the Severe Impairment Battery. 1H-MRS may be a useful diagnostic tool in future longitudinal studies to measure AD progression in persons with DS. In particular, NAA and the NAA/MI ratio is sensitive to the functional status of adults with DS, including prior to dementia.

Metabolic Syndrome and Phthalate Metabolites in Adults Stratified by Sex and Menopausal Status from NHANES (2003-2010)

Metabolic Syndrome and Phthalate Metabolites in Adults Stratified by Sex and Menopausal Status from NHANES (2003-2010)

Reduction in urinary organophosphate pesticide metabolites in adults after a week-long organic diet

BackgroundConventional food production commonly uses organophosphate (OP) pesticides, which can have negative health effects, while organic food is deemed healthier because it is produced without these pesticides. Studies suggest that organic food consumption may significantly reduce OP pesticide exposure in children who have relatively higher pesticide exposure than adults due to their different diets, body weight, behaviour and less efficient metabolism. ObjectivesA prospective, randomised, crossover study was conducted to determine if an organic food diet reduces organophosphate exposure in adults. MethodsThirteen participants were randomly allocated to consume a diet of at least 80% organic or conventional food for 7 days and then crossed over to the alternate diet. Urinary levels of six dialkylphosphate metabolites were analysed in first-morning voids collected on day 8 of each phase using GC–MS/MS with detection limits of 0.11–0.51μg/L. ResultsThe mean total DAP results in the organic phase were 89% lower than in the conventional phase (M=0.032 [SD=0.038] and 0.294 [SD=0.435] respectively, p=0.013). For total dimethyl DAPs there was a 96% reduction (M=0.011 [SD=0.023] and 0.252 [SD=0.403] respectively, p=0.005). Mean total diethyl DAP levels in the organic phase were half those of the conventional phase (M=0.021 [SD=0.020] and 0.042 [SD=0.038] respectively), yet the wide variability and small sample size meant the difference was not statistically significant. ConclusionsThe consumption of an organic diet for one week significantly reduced OP pesticide exposure in adults. Larger scale studies in different populations are required to confirm these findings and investigate their clinical relevance.

Urinary concentrations of organophosphate pesticide metabolites in adults in Israel: Demographic and dietary predictors

Exposure to organophosphate pesticides (OPs) in agricultural and urban populations has been associated with a range of adverse health effects. The purpose of the current study was to estimate exposure to OPs in the general adult population in Israel and to determine dietary and demographic predictors of exposure. We measured six non-specific organophosphate pesticide metabolites (dialkyl phosphates) in urine samples collected from 247 Israeli adults from the general population. We collected detailed demographic and dietary data from these individuals, and explored associations between demographic and dietary characteristics and urinary dialkyl phosphate concentrations. OP metabolites were detectable in all urine samples. Concentrations of several dialkyl phosphate metabolites (dimethylphosphate, dimethylthiophosphate, diethylphosphate) were high in our study population relative to the general populations in the US and Canada and were comparable to those reported in 2010 in France. Total dialkyl phosphates were higher in individuals with fruit consumption above the 75th percentile. In a multivariate analysis, total molar dialkyl phosphate concentration increased with age and was higher in individuals with high income compared to individuals with the lowest income. Total diethyl metabolite concentrations were higher in females and in study participants whose fruit consumption was above the 75th percentile. In conclusion, we found that levels of exposure to OP pesticides were high in our study population compared to the general population in the US and Canada and that intake of fruits is an important source of exposure.

Comparative Effects of Certain Igrs on the Carbohydrates of Hemolymph and Fat Body of the Desert Locust, Schistocerca Gregaria (Orthoptera: Acrididae)

Newly molted last (5th) instar of the desert locust, Schistocerca gregaria (Forsk.), was treated through fresh plant food with 2 concentrations: high (1000.0 ppm) or low (62.5 ppm) of 3 IGRs: pyriproxyfen, tebufenozide, and lufenuron. Carbohydrate content was determined in the hemolymph and in the fat body of the early-aged, mid-aged, and late-aged 5th instar, as well as of 1- and 4-d old adult females. Pyriproxyfen prevented the nymphs to gain normal carbohydrate content in the hemolymph. In contrast, tebufenozide induced the nymphs to gain more carbohydrates. Lufenuron caused hemolymph carbohydrate content to decrease slightly in the early-aged nymphs but increased it in older nymphs. All three IGRs significantly affected the hemolymph carbohydrate content of nymphs of all ages. Pyriproxyfen drastically reduced the carbohydrate content of the hemolymph of 1-day old adults, but at the low concentration caused it to increase in the 4-day old adults. Tebufenozide induced adults to attain excess carbohydrates in the hemolymph at the low concentration level only. Lufenuron at both concentrations promoted increases of this metabolite in adults regardless of their age. Pyriproxyfen treatments of nymphs resulted in reduced carbohydrate content in the fat body of 1-d old adults, whereas tebufenozide and lufenuron at both concentrations induced increases in the carbohydrate content in fat bodies of 1- and 4-day old adults. The data from this study suggest that pyriproxyfen, tebufenozide and lufenuron alter the metabolism and storage of carbohydrate in nymphs and adults of the desert locust S. gregaria. Because carbohydrate is for all biological processes in nymphs and adults, these IGRs have considerable promise for use in the control of this destructive pest.

Variability on urinary excretion of chlorogenic acid compounds and metabolites in humans after overnight fasting and under controlled diets

Large intra‐ and inter‐individual variabilities have been observed in previous studies evaluating polyphenols bioavailability in humans. The present study evaluated the intra‐ and inter‐individual variations on the urinary excretion of chlorogenic acids (CGA) and metabolites in adults (n=12), in 5 separate days, after 10h fasting and a 48h controlled phenolic free‐diet. A total of 22 compounds (359.74 ± 197.90 μmol) were identified in urine by HPLC/MS, including 6 CGA and 16 phenolic acids, varying from 1 to 10 fold for the same subject intra‐day. Only 0.36 ± 0.35 μmol of total CGA were excreted in urine, varying from 1 to 7 fold for the same subject intra‐day. A large inter‐individual variation was also observed for all compounds. The largest variation was observed for p‐coumaric acid, followed by 4‐caffeoylquinic and 3‐(4’‐hydroxyphenyl) propionic acids, whereas benzoic, hippuric and 2,4‐dihydroxybenzoic acids showed the lowest variation. The patterns of CGA and metabolites excretion were also remarkably different among subjects, but remained similar in different days for the same subjects. Concluding, the inter‐individual variability on CGA metabolism seems to be more expressive when compared to intra‐individual variability. Our results also suggest the need for long washout periods for CGA and that their metabolization routs may vary according to individuals, which should be thoroughly investigated. Financial Support: CNPQ and FAPERJ.

Pharmacokinetics of Mycophenolate Mofetil and Sirolimus in Children

This review summarizes the pharmacokinetics in children and youths of 2 commonly used immunosuppressive drugs, mycophenolate mofetil (MMF) and sirolimus (Sir), as presented at the IATDMCT 2007 conference. The review focuses on the developmental changes of drug disposition during childhood and adolescence. Regarding mycophenolate mofetil, the authors were unable to demonstrate age dependency of MMF in combination with cyclosporine. By contrast, there was an inverse relationship between age and the dose-normalized mycophenolate (MPA) area-under-the-time-concentration curve (AUC) in children who received concomitant tacrolimus (Tac). Dose-normalized MPA AUCs were higher than commonly observed in adult patients. It can be hypothesized that the age dependency is related to developmental changes in the expression of the UDP-glucuronosyltransferases. Sirolimus half-life and mean residence time (MRT) are shorter than in adults. Similar to that in adults, there is a profound drug-drug interaction between cyclosporine and Sir. In our own experience, Sir was started at 0.13 +/- 0.05 mg/kg/day. The average Sir AUC was 64.9 +/- 29.7 ng*h/mL. The median (range) AUC for each metabolite was as follows: 12-hydroxy-Sir, 7.6 (0.2-18.8); 46-hydroxy-Sir, 3.1 (0.0-12.4); 24-hydroxy-Sir, 4.3 (0.0-12.6); piperidine-hydroxy-Sir, 3.5 (0.0-8.3); 39-desmethyl-Sir, 3.6 (0.0-11.3); 16-desmethyl-Sir, 5.0 (0.1-9.9); and di-hydroxy-Sir, 4.3 (0.0-32.5) ng*h/mL. Of the total metabolite AUC, 77.5% was due to hydroxylated metabolites, while 39-O-desmethyl Sir (the main metabolite in adults) comprised only 8.4% of the metabolites. This is clinically relevant, as 39-O-desmethyl Sir shows 86% to 127% cross-reactivity with the Sir immunoassay. Metabolites reached a median AUC of 60% of that of Sir, but the range was 2.6% to 136%. The age dependency of Sir metabolite formation was confirmed in a human liver microsome model. On the basis of the age dependency of piperidine-hydroxy Sir, the authors postulate that the ontogeny of the drug disposition can be largely explained by developmental changes of the CYP2C8 expression. In conclusion, both Sir and MMF drug disposition vary in children and adolescents from adult patients, most likely because of developmental changes of biliary transporters and metabolic enzymes.

Optimization of Immunosuppressive Drug Monitoring in Children

Background The metabolism of drugs in children differs from adults, although pediatric pharmacokinetic (PK) studies remain scarce. Many of the drugs are metabolized by polymorphically expressed enzymes (cytochrome P450 [CYP450]; glucuronyl transferase [GT]) and/or transported by drug transporters (ABC and SLC families). In children, there is added complexity because of the age dependency of drug metabolism. This review addresses the age dependency of drug metabolism in childhood on the basis of routine PK monitoring. Methods Standard pharmacokinetic studies in pediatric renal transplant recipients were analyzed to study drug-drug interactions between mycophenolic acid and cyclosporine on the one hand, and tacrolimus and sirolimus on the other hand. The exposure was compared with age. We also studied sirolimus metabolites, both by mass spectrometry as well as using human liver microsomes. Results We demonstrated age dependency for MPA exposure. Independent of the concomitant medication, infants required approximately twice as much drug for the same exposure. The drug-drug interaction between sirolimus and tacrolimus demonstrated age dependency. Sirolimus metabolites showed a remarkably different pattern in children. Whereas 39-O-desmethyl sirolimus is the most prevalent metabolite in adults, we found 77.5% hydroxylated metabolites in children. Similarly, pediatric human liver microsomes produced 86.1% hydroxylated metabolites. Conclusions Our long-term objective is to develop evidence-based guidelines for age-appropriate drug dosing of all drugs commonly used during childhood and adolescence, based on pharmacokinetically/pharmacogenetically determined drug exposure to maximize therapeutic yield while minimizing toxicity. The potential need for lifelong medications warrants efforts to minimize toxicity in chronically ill pediatric patients.