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Reversed-Phase Liquid Chromatography (RPLC) is a common liquid chromatographic mode used for the control of pharmaceutical compounds during their drug life cycle. Nevertheless, determining the optimal chromatographic conditions that enable this separation is time consuming and requires a lot of lab work. Quantitative Structure Retention Relationship models (QSRR) are helpful for doing this job with minimal time and cost expenditures by predicting retention times of known compounds without performing experiments. In the current work, several QSRR models were built and compared for their adequacy in predicting the retention times. The regression models were based on a combination of linear and non-linear algorithms such as Multiple Linear Regression, Support Vector Regression, Least Absolute Shrinkage and Selection Operator, Random Forest, and Gradient Boosted Regression. Models were built for five pH conditions, i.e., at pH 2.7, 3.5, 6.5, and 8.0. In the end, the model predictions were combined using stacking and the performances of all models were compared. The k-nearest neighbor-based application domain filter was established to assess the reliability of the prediction for further compound prioritization. Altogether, this study can be insightful for analytical chemists working with RPLC to begin with the computational prediction modeling such as QSRR to predict the separation of small molecules.

Aflatoxins (AFs) frequently contaminate food and animal feeds, especially in (sub) tropical countries. If animals consume contaminated feeds, AFs (mainly aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1), G2 (AFG2) and their major metabolites aflatoxin M1 (AFM1) and M2 (AFM2)) can be transferred to edible tissues and products, such as eggs, liver and muscle tissue and milk, which ultimately can reach the human food chain. Currently, the European Union has established a maximum level for AFM1 in milk (0.05 µg kg−1). Dietary adsorbents, such as bentonite clay, have been used to reduce AFs exposure in animal husbandry and carry over to edible tissues and products. To investigate the efficacy of adding bentonite clay to animal diets in reducing the concentration of AFB1, AFB2, AFG1, AFG2, and the metabolites AFM1 and AFM2 in animal-derived foods (chicken muscle and liver, eggs, and cattle milk), chicken and cattle plasma and cattle ruminal fluid, a sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been developed. High-throughput sample preparation procedures were optimized, allowing the analysis of 96 samples per analytical batch and consisted of a liquid extraction using 1% formic acid in acetonitrile, followed by a further clean-up using QuEChERS (muscle tissue), QuEChERS in combination with Oasis® Ostro (liver tissue), Oasis® Ostro (egg, plasma), and Oasis® PRiME HLB (milk, ruminal fluid). The different procedures were validated in accordance with European guidelines. As a proof-of-concept, the final methods were used to successfully determine AFs concentrations in chicken and cattle samples collected during feeding trials for efficacy and safety evaluation of mycotoxin detoxifiers to protect against AFs as well as their carry-over to animal products.

A major problem with dietary assessments is their subjective nature. Untargeted metabolomics and new technologies can shed light on this issue and provide a more complete picture of dietary intake by measuring the profile of metabolites in biological samples. Oranges are one of the most consumed fruits in the world, and therefore one of the most studied for their properties. The aim of this work was the application of untargeted metabolomics approach with the novel combination of ion mobility separation coupled to high resolution mass spectrometry (IMS-HRMS) and study the advantages that this technique can bring to the area of dietary biomarker discovery, with the specific case of biomarkers associated with orange consumption (Citrus reticulata) in plasma samples taken during an acute intervention study (consisting of a randomized, controlled crossover trial in healthy individuals). A total of six markers of acute orange consumption, including betonicines and conjugated flavonoids, were identified with the experimental data and previous literature, demonstrating the advantages of ion mobility in the identification of dietary biomarkers and the benefits that an additional structural descriptor, as the collision cross section value (CCS), can provide in this area.

Purpose Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Methods Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. Results No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4–9.3 and 4.7–7.3 h, maximum concentration of 795.6–3742.6 and 493.3–3746 ng/mL, half-life of 1.7–5.9 and 2.3–6.9 h, and 0–12 h area under the curve of 4518.7–20,781.4 and 1987.7–22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30–60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. Conclusions Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.

Background and Objective Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL ® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. Methods A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1 week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography–diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration ( C max ), area under concentration time curve from time of administration (0) to time (t) [AUC 0-t ] or to infinity ∞, [AUC 0-∞ ],  half-life ( T ½ ) and time to reach C max ( T max ) were calculated. Results The test micellar astaxanthin reached a C max of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. Conclusion Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Background Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization. Methods In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects ( n  = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [ 14 C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated. Results After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3–99.4%) within 14 days, with 86.3% (84.8–88.1%) excreted via feces and 11.6% (9.5–13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo. Conclusion Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose). Clinical trial registration ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017). Plain Language Summary Eliapixant is a drug that acts on structures in the body called P2X3 receptors that are involved in several conditions, including chronic cough, overactive bladder, and endometriosis-related pain. When evaluating a new drug, it is important to know how it is being removed from the body by natural mechanisms. We performed a study in which six healthy male volunteers took a single dose of eliapixant, and we investigated what happened to the drug after it was taken. We measured the amount of eliapixant in the volunteers’ blood, urine, and feces, and also measured the compounds formed when eliapixant was broken down naturally by the body (“metabolites”). We also used human cells in the laboratory to investigate how the different metabolites of eliapixant are formed. Almost three-quarters of eliapixant in the blood had not been broken down at all, while the remaining one-quarter had been converted into many different metabolites. A total of 2 weeks after taking eliapixant, almost all of it had been converted to metabolites and eliminated from the body (mostly in feces, but also a small amount in urine). The most important organ for breaking down eliapixant is the liver. The information from this study will help doctors determine whether eliapixant is likely to interfere with other drugs taken simultaneously, and whether patients with liver or kidney problems might take longer than healthy people to remove it from their bodies.

PurposeCYP3A4, CYP2C19, and CYP3A5 are primarily involved in the metabolism of cilostazol. We investigated the effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its two active metabolites.MethodsThirty-three healthy Korean volunteers were administered a single 100-mg oral dose of cilostazol. The concentrations of cilostazol and its active metabolites (OPC-13015 and OPC-13213) in the plasma were determined by HPLC-MS/MS.ResultsAlthough the pharmacokinetic parameters for cilostazol were similar in different CYP2C19 and CYP3A5 genotypes, CYP2C19PM subjects showed significantly higher AUC0-∞ for OPC-13015 and lower for OPC-13213 compared to those in CYP2C19EM subjects (P < 0.01 and P < 0.001, respectively). Pharmacokinetic differences in OPC-13015 between CYP3A5 non-expressors and expressors were significant only within CYP2C19PM subjects. The amount of cilostazol potency-adjusted total active moiety was the greatest in subjects with CYP2C19PM-CYP3A5 non-expressor genotype.ConclusionThese results suggest that CYP2C19 and CYP3A5 genetic polymorphisms affect the plasma exposure of cilostazol total active moiety. CYP2C19 plays a crucial role in the biotransformation of cilostazol.

Olanzapine (OLZ) is the first-line, cost–effectiveness treatment for schizophrenia in China. A quantitative ultrahigh performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method for determination of OLZ in human plasma was developed. LC separation was achieved on Waters XBrige C column. ESI was involved and multiple reaction monitoring transitions were at 313.2→256.1 for OLZ and 316.2→256.1 IS (d3-OLZ). The linear range was 0.1–20 ng/ml with LLOQ of 0.1 ng/ml. Accuracy and precision were within 10%. The validated method was successfully applied to a bioequivalence study of OLZ disintegrating tablets at dose of 5 mg with 100% reproducibility evaluated by incurred sample reanalysis. A robust validated method was developed for quantitation of OLZ in human plasma.

Ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC–HRMS) variants currently represent the best tools to tackle the challenges of complexity and lack of comprehensive coverage of the metabolome. UHPLC offers flexible and efficient separation coupled with high-sensitivity detection via HRMS, allowing for the detection and identification of a broad range of metabolites. Here we discuss current common strategies for UHPLC–HRMS-based metabolomics, with a focus on expanding metabolome coverage.This Review surveys ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC–HRMS), a highly sensitive, high-throughput technique that is used for analyzing a broad range of metabolites.

A method to quantitate doravirine (MK-1439) in human plasma has been developed to support human clinical trials designed to evaluate the safety, pharmacokinetics and efficacy of the compound. The analyte was extracted using liquid–liquid extraction, separated on a reverse phase HPLC column, and detected on an API-4000 mass spectrometer using a Turbo-Ion spray source in positive ionization mode coupled with multiple reaction monitoring mode was used for quantification. The dynamic range for the assay was 0.02–10 ng/ml using 100 μl of human plasma. The assay was found to be sensitive, selective and reproducible and applied to support the doravirine clinical development program.