Combined in vivo metabolic effects of quetiapine and methadone in brain and blood of rats.

Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225-296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered.

Assessment of XCMS Optimization Methods with Machine-Learning Performance.

The metabolomics field is under rapid development. In particular, biomarker identification and pathway analysis are growing, as untargeted metabolomics is usable for discovery research. Frequently, new processing and statistical strategies are proposed to accommodate the increasing demand for robust and standardized data. One such algorithm is XCMS, which processes raw data into integrated peaks. Multiple studies have tried to assess the effect of optimizing XCMS parameters, but it is challenging to quantify the quality of the XCMS output. In this study, we investigate the effect of two automated optimization tools (Autotuner and isotopologue parameter optimization (IPO)) using the prediction power of machine learning as a proxy for the quality of the data set. We show that optimized parameters outperform default XCMS settings and that manually chosen parameters by liquid chromatography-mass spectrometry (LC-MS) experts remain the best. Finally, the machine-learning approach of quality assessment is proposed for future evaluations of newly developed optimization methods because its performance directly measures the retained signal upon preprocessing.

The Relationship between In Vitro and In Vivo Starch Digestion Kinetics of Breads Varying in Dietary Fibre.

The relationship between in vitro and in vivo starch digestion kinetics was studied in portal vein catheterised pigs fed breads varying in dietary fibre (DF) content and composition. The breads were a low DF white wheat bread, two high DF whole grain rye breads without and with whole kernels and two experimental breads with added arabinoxylan or oat ß-glucan concentrates, respectively. In vitro, samples were collected at 0, 5, 10, 15, 30, 60, 120 and 180 min and the cumulative hydrolysis curve for starch was modelled, whereas the in vivo cumulative absorption models for starch were based on samples taken every 15 min up to 60 min and then every 30 min up to 240 min. The starch hydrolysis rate in vitro (0.07 to 0.16%/min) was far higher than the rate of glucose appearance in vivo (0.017 to 0.023% absorbed starch/min). However, the ranking of the breads was the same in vitro and in vivo and there was a strong relationship between the kinetic parameters.

Postprandial PYY increase by resistant starch supplementation is independent of net portal appearance of short-chain fatty acids in pigs.

Increased dietary fiber (DF) fermentation and short-chain fatty acid (SCFA) production may stimulate peptide tyrosine-tyrosine (PYY) secretion. In this study, the effects of hindgut SCFA production on postprandial PYY plasma levels were assessed using different experimental diets in a porto-arterial catheterized pig model. The pigs were fed experimental diets varying in source and levels of DF for one week in 3×3 Latin square designs. The DF sources were whole-wheat grain, wheat aleurone, rye aleurone-rich flour, rye flakes, and resistant starch. Postprandial blood samples were collected from the catheters and analyzed for PYY levels and net portal appearance (NPA) of PYY was correlated to NPA of SCFA. No significant effects of diets on NPA of PYY were observed (P > 0.05), however, resistant starch supplementation increased postprandial NPA of PYY levels by 37 to 54% compared with rye-based and Western-style control diets (P = 0.19). This increase was caused by higher mesenteric artery and portal vein PYY plasma levels (P < 0.001) and was independent of SCFA absorption (P > 0.05). The PYY levels were higher in response to the second daily meal compared with the first daily meal (P < 0.001), but similar among diets (P > 0.10). In conclusion, the increased postprandial PYY responses in pigs fed with different levels and sources of DF are not caused by an increased SCFA absorption and suggest that other mechanisms such as neural reflexes and possibly an increased flow of digesta in the small intestine may be involved. The content of DF and SCFA production did not affect PYY levels.

A metabolomics approach used to profile plasma from portal-arterial pigs revealed differences between breads incurred by dietary fibre and protein contents.

A liquid chromatography-MS (LC-MS) metabolomics analysis of plasma from portal-arterial catheterised pigs fed breads prepared with whole-grain rye or wheat flour with added concentrated arabinoxylan (AX) or ß-glucan (BG) was conducted. Comparison of the effects of concentrated fibres with whole grains has received little attention. Six female catheterised pigs were given two white wheat breads with wheat AX or oat BG, two rye breads with ground rye (GR) or intact rye kernels (RK), and a control white wheat bread (WF) on separate occasions in a randomised cross-over design. The amount of available carbohydrate was similar for the five breads but varied in the content of protein. Plasma was collected continuously for 4 h after feeding. Glucose levels in the portal vein were reduced postprandially in response to the AX, GR and RK breads that had high contents of AX compared with WF bread (P < 0·03). AX and RK breads further tended to decrease plasma levels of some lysophosphatidylcholine species (P ≤ 0·10). The abundance of amino acids in plasma correlated with the protein contents in the breads and leucine uptake significantly affected insulin secretion in the mesenteric artery. In conclusion, the present study revealed that concentrated AX in wheat bread had similar positive effects as whole-grain rye bread on glucose and lipid metabolism.