scholarly journals DETERMINATION OF TERIFLUNOMIDE ACROSS A WIDE DYNAMIC CONCENTRATION RANGE IN HUMAN PLASMA BY LC–MS/MS

2019 ◽  
Vol 16 (32) ◽  
pp. 608-620
Author(s):  
Natalia E. MOSKALEVA ◽  
Natalia V. MESONZHNIK ◽  
Roman M. KUZNETSOV ◽  
Pavel A. MARKIN ◽  
Svetlana A. APPOLONOVA
Keyword(s):  
Blood Plasma ◽  
High Performance ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
The Body ◽  
Human Blood Plasma ◽  
Measured Concentration ◽  
Wide Range ◽  
The Difference ◽  
Acquity Uplc

Leflunomide is an antirheumatic drug with anti-inflammatory and antirheumatic properties, it is rapidly metabolized in the body to the active metabolite teriflunomide, which causes its pharmacological activity. At the usual 20-mg daily dosage of leflunomide, the expected teriflunomide plasma concentration is about 35 μg/ml. The pharmacokinetics of the drug is characterized by a large interindividual variability and a long half-life, which in combination with possible side effects creates the need to control the concentration of teriflunomide in the blood plasma. Teriflunomide may increase the risk of fetal death or teratogenic effects when administered to pregnant women. Teriflunomide plasma concentrations less than 0.02 μg/ml are preferred for patients anticipating pregnancy. In this study, a sensitive and high-performance method for analyzing teriflunomide in human blood plasma in a wide range of concentrations was developed and validated using a triple quadrupole liquid chromatography-mass spectrometer (HPLC-MS/MS). Sample preparation was performed by protein precipitation with acetonitrile, followed by chromatographic separation using an Acquity UPLC BEN C8 1.7 mm, 2.1 × 50 mm column (Waters, USA). D4-teriflunomide was used as an internal standard. The developed method was validated in the concentration range from 0.001 μg/ml to 200 μg/ml teriflunomide in plasma. Accuracy (%), defined as the difference between the nominal and measured concentration and reproducibility (coefficient of variation CV) ranged from -5.02% to 5.00% and from 0.47% to 9.30%, respectively, within the series and between series of samples. The developed method was successfully used to analyze volunteer blood plasma samples after taking 20 mg of leflunomide.

scholarly journals Development and validation of an improved HPLC-UV method for simultaneous determination of lamotrigine and oxcarbazepine and its active metabolite 10,11-dihydro-10-hydroxycarbazepine in human blood plasma and comparison with an UHPLC-MS/MS method

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Siyao Jin ◽  
Qing Zhao ◽  
Dongjie Zhang ◽  
Zhigang Zhao ◽  
Shenghui Mei
Keyword(s):  
Liquid Chromatography ◽  
Blood Plasma ◽  
Simultaneous Determination ◽  
Human Blood ◽  
High Performance ◽  
Internal Standard ◽  
Ultra Performance Liquid Chromatography ◽  
Human Blood Plasma ◽  
Elution Time

AbstractLamotrigine (LTG) and oxcarbazepine (OXC) are first-line drugs for epilepsy treatment. Their large pharmacokinetics variabilities and relations between efficacy and toxicity and blood plasma concentration require routine monitoring for dose adjustment. In this study, we developed and validated a simple, accurate, and reliable method for simultaneous determination of LTG, OXC and 10,11-dihydro-10-hydroxycarbazepine (MHD) in human blood plasma by high-performance liquid chromatography-ultraviolet detection (HPLC-UV) with a simple one-step protein precipitation using methanol (1% acetic acid) and 15 min elution time under isocratic elution at 1 mL/min. Calibration range was 2.4 to 120 mg/L for LTG, OXC, and MHD. The intra-day and inter-day bias were − 8.84 to 4.18%, and the imprecision was less than 8.08% for all analytes. The internal standard (fluconazole) normalized recovery was 96.30 to 107.69% for LTG, 98.51 to 111.04% for MHD, and 95.04 to 109.86% for OXC. A total of 186 LTG samples and 25 MHD samples were used to evaluate the agreement between HPLC-UV and ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) by Passing-Bablok regression and Bland-Altman plot. The mean bias and the 95% limits of agreement (95% LOA) of the two measurements were 0.575 mg/L and − 1.238 to 2.387 mg/L for LTG (n = 186) and − 1.222 mg/L and − 8.271 to 5.827 mg/L for MHD (n = 25), which indicated the UV method was comparable with the MS method for LTG and MHD analysis.

scholarly journals Plasma radio-metabolite analysis of PET tracers for dynamic PET imaging: TLC and autoradiography

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Fiona Li ◽  
Justin W. Hicks ◽  
Lihai Yu ◽  
Lise Desjardin ◽  
Laura Morrison ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Blood Plasma ◽  
Kinetic Parameters ◽  
High Performance ◽  
The Body ◽  
Accurate Estimation ◽  
Dynamic Pet ◽  
Arterial Concentration ◽  
In Blood Plasma

Abstract Background In molecular imaging with dynamic PET, the binding and dissociation of a targeted tracer is characterized by kinetics modeling which requires the arterial concentration of the tracer to be measured accurately. Once in the body the radiolabeled parent tracer may be subjected to hydrolysis, demethylation/dealkylation and other biochemical processes, resulting in the production and accumulation of different metabolites in blood which can be labeled with the same PET radionuclide as the parent. Since these radio-metabolites cannot be distinguished by PET scanning from the parent tracer, their contribution to the arterial concentration curve has to be removed for the accurate estimation of kinetic parameters from kinetic analysis of dynamic PET. High-performance liquid chromatography has been used to separate and measure radio-metabolites in blood plasma; however, the method is labor intensive and remains a challenge to implement for each individual patient. The purpose of this study is to develop an alternate technique based on thin layer chromatography (TLC) and a sensitive commercial autoradiography system (Beaver, Ai4R, Nantes, France) to measure radio-metabolites in blood plasma of two targeted tracers—[18F]FAZA and [18F]FEPPA, for imaging hypoxia and inflammation, respectively. Results Radioactivity as low as 17 Bq in 2 µL of pig’s plasma can be detected on the TLC plate using autoradiography. Peaks corresponding to the parent tracer and radio-metabolites could be distinguished in the line profile through each sample (n = 8) in the autoradiographic image. Significant intersubject and intra-subject variability in radio-metabolites production could be observed with both tracers. For [18F]FEPPA, 50% of plasma activity was from radio-metabolites as early as 5-min post injection, while for [18F]FAZA, significant metabolites did not appear until 50-min post. Simulation study investigating the effect of radio-metabolite in the estimation of kinetic parameters indicated that 32–400% parameter error can result without radio-metabolites correction. Conclusion TLC coupled with autoradiography is a good alternative to high-performance liquid chromatography for radio-metabolite correction. The advantages of requiring only small blood samples (~ 100 μL) and of analyzing multiple samples simultaneously, make the method suitable for individual dynamic PET studies.

scholarly journals Development and Validation of a Sensitive, Specific and Reproducible UPLC-MS/MS Method for the Quantification of OJT007, A Novel Anti-Leishmanial Agent: Application to a Pharmacokinetic Study

2021 ◽  
Vol 18 (9) ◽  
pp. 4624
Author(s):  
Maria Rincon Nigro ◽  
Jing Ma ◽  
Ololade Tosin Awosemo ◽  
Huan Xie ◽  
Omonike Arike Olaleye ◽  
...  
Keyword(s):  
Formic Acid ◽  
High Performance ◽  
Leishmania Major ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Plasma ◽  
The Matrix ◽  
Liquid Chromatography Tandem Mass ◽  
Positive Mode ◽  
Acquity Uplc

OJT007 is a methionine aminopeptidase 1 (MetAP1) inhibitor with potent anti-proliferative effects against Leishmania Major. In order to study its pharmacokinetics as a part of the drug development process, a sensitive, specific, and reproducible ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated. Voriconazole was used as the internal standard to generate standard curves ranging from 5 to 1000 ng/mL. The separation was achieved using a UPLC system equipped with an Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm) with 0.1% formic acid in acetonitrile and 0.1% formic acid in water as the mobile phase under gradient elution at a flow rate of 0.4 mL/min. The mass analysis was performed with a 4000 QTRAP® mass spectrometer using multiple-ion reaction monitoring (MRM) in the positive mode, with the transition of m/z 325 → m/z 205 for OJT007 and m/z 350 → m/z 101 for voriconazole. The intra- and inter-day precision and accuracy were within ±15%. The mean extraction recovery and the matrix effect were 95.1% and 7.96%, respectively, suggesting no significant matrix interfering with the quantification of the drug in rat plasma. This study was successfully used for the pharmacokinetic evaluation of OJT007 using the rat as an animal model.

scholarly journals Distribution of Saponins in the Sea Cucumber Holothuria lessoni; the Body Wall Versus the Viscera, and Their Biological Activities

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 423 ◽  
Author(s):  
Yadollah Bahrami ◽  
Wei Zhang ◽  
Christopher M. M. Franco
Keyword(s):  
High Performance ◽  
Sea Cucumber ◽  
Body Wall ◽  
Biological Activities ◽  
Folk Medicine ◽  
Pharmaceutical Products ◽  
The Body ◽  
Triterpene Glycosides ◽  
Partition Chromatography ◽  
Wide Range

Sea cucumbers are an important ingredient of traditional folk medicine in many Asian countries, which are well-known for their medicinal, nutraceutical, and food values due to producing an impressive range of distinctive natural bioactive compounds. Triterpene glycosides are the most abundant and prime secondary metabolites reported in this species. They possess numerous biological activities ranging from anti-tumour, wound healing, hypolipidemia, pain relieving, the improvement of nonalcoholic fatty livers, anti-hyperuricemia, the induction of bone marrow hematopoiesis, anti-hypertension, and cosmetics and anti-ageing properties. This study was designed to purify and elucidate the structure of saponin contents of the body wall of sea cucumber Holothuria lessoni and to compare the distribution of saponins of the body wall with that of the viscera. The body wall was extracted with 70% ethanol, and purified by a liquid-liquid partition chromatography, followed by isobutanol extraction. A high-performance centrifugal partition chromatography (HPCPC) was conducted on the saponin-enriched mixture to obtain saponins with a high purity. The resultant purified saponins were analyzed using MALDI-MS/MS and ESI-MS/MS. The integrated and hyphenated MS and HPCPC analyses revealed the presence of 89 saponin congeners, including 35 new and 54 known saponins, in the body wall in which the majority of glycosides are of the holostane type. As a result, and in conjunction with existing literature, the structure of four novel acetylated saponins, namely lessoniosides H, I, J, and K were characterized. The identified triterpene glycosides showed potent antifungal activities against tested fungi, but had no antibacterial effects on the bacterium Staphylococcus aureus. The presence of a wide range of saponins with potential applications is promising for cosmeceutical, medicinal, and pharmaceutical products to improve human health.

ANP kinetics in normal men: in vivo measurement by a tracer method and correlation with sodium intake

1993 ◽  
Vol 264 (3) ◽  
pp. F480-F489 ◽  
Author(s):  
G. Iervasi ◽  
A. Clerico ◽  
S. Berti ◽  
A. Pilo ◽  
F. Vitek ◽  
...  
Keyword(s):  
High Performance ◽  
Sodium Intake ◽  
Mean Transit Time ◽  
Normal Subjects ◽  
The Body ◽  
Metabolic Clearance ◽  
Healthy Human ◽  
Large Space ◽  
Wide Range

125I-labeled atrial natriuretic peptide (ANP) was bolus injected into seven healthy human male subjects on an unrestricted diet (sodium intake ranging from 80 to 300 mmol/day). A high-performance liquid chromatographic procedure was used to purify the labeled hormone and the principal labeled metabolites in venous plasma samples collected up to 50 min after injection. The main ANP kinetic parameters were derived from the disappearance curves of the 125I-ANP, which were satisfactorily fitted by a biexponential function in all subjects. Newly produced ANP initially distributes in a large space (plasma-equivalent volume is 12.1 +/- 3.6 l/m2 body surface); the hormone rapidly leaves this sampling space through both degradation and distribution in peripheral spaces, as indicated by the single-pass mean transit time through the sampling space (3.9 +/- 1.2 min). The mean residence time in the body (22.7 +/- 23.1 min) and the plasma-equivalent total distribution volume (30.9 +/- 12.0 l/m2) indicate that ANP is also widely distributed outside the initial space. Metabolic clearance rate (MCR) values were distributed across a wide range (from 740 to 2,581 ml.min-1 x m-2) and were shown to correlate strongly with the daily urinary excretion of sodium. These results indicate that: 1) newly produced ANP is rapidly distributed and degraded, 2) the body pool of the hormone can be considered as a combination of two exchanging spaces, 3) circulating ANP is < or = 1/15 of the body pool, and 4) MCR of ANP is closely related to sodium intake, at least in normal subjects on a free sodium intake diet.

scholarly journals Delta-S-Cys-Albumin: A Lab Test that Quantifies Cumulative Exposure of Archived Human Blood Plasma and Serum Samples to Thawed Conditions

2019 ◽  
Vol 18 (10) ◽  
pp. 2121-2137 ◽  
Author(s):  
Joshua W. Jeffs ◽  
Nilojan Jehanathan ◽  
Stephanie M. F. Thibert ◽  
Shadi Ferdosi ◽  
Linda Pham ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Relative Abundance ◽  
Maximum Level ◽  
Cumulative Exposure ◽  
Intact Protein ◽  
Human Blood Plasma ◽  
Serum Samples ◽  
Protein Mass ◽  
Before And After ◽  
The Difference

Exposure of blood plasma/serum (P/S) to thawed conditions (> −30 °C) can produce biomolecular changes that skew measurements of biomarkers within archived patient samples, potentially rendering them unfit for molecular analysis. Because freeze-thaw histories are often poorly documented, objective methods for assessing molecular fitness before analysis are needed. We report a 10-μl, dilute-and-shoot, intact-protein mass spectrometric assay of albumin proteoforms called “ΔS-Cys-Albumin” that quantifies cumulative exposure of archived P/S samples to thawed conditions. The relative abundance of S-cysteinylated (oxidized) albumin in P/S increases inexorably but to a maximum value under 100% when samples are exposed to temperatures > −30 °C. The difference in the relative abundance of S-cysteinylated albumin (S-Cys-Alb) before and after an intentional incubation period that drives this proteoform to its maximum level is denoted as ΔS-Cys-Albumin. ΔS-Cys-Albumin in fully expired samples is zero. The range (mean ± 95% CI) observed for ΔS-Cys-Albumin in fresh cardiac patient P/S (n = 97) was, for plasma 12–29% (20.9 ± 0.75%) and for serum 10–24% (15.5 ± 0.64%). The multireaction rate law that governs S-Cys-Alb formation in P/S was determined and shown to predict the rate of formation of S-Cys-Alb in plasma and serum samples—a step that enables back-calculation of the time at which unknown P/S specimens have been exposed to room temperature. A blind challenge demonstrated that ΔS-Cys-Albumin can detect exposure of groups (n = 6 each) of P/S samples to 23 °C for 2 h, 4 °C for 16 h, or −20 °C for 24 h—and exposure of individual specimens for modestly increased times. An unplanned case study of nominally pristine serum samples collected under NIH-sponsorship demonstrated that empirical evidence is required to ensure accurate knowledge of archived P/S biospecimen storage history.

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