Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

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Effect of the intramolecular hydrogen bond in the active metabolite analogs of leflunomide for blocking the Plasmodium falciparum dihydroorotate dehydrogenase enzyme: QTAIM, NBO, and docking study

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200527133126 ◽

2020 ◽

Vol 16 ◽

Author(s):

Reihaneh Heidarian ◽

Mansoureh Zahedi-Tabrizi

Keyword(s):

Hydrogen Bond ◽

Plasmodium Falciparum ◽

Molecular Orbital ◽

Intramolecular Hydrogen Bond ◽

Active Metabolite ◽

Chemical Hardness ◽

Dihydroorotate Dehydrogenase ◽

Molecular Orbital Analysis ◽

Intramolecular Hydrogen ◽

Orbital Analysis

: Leflunomide (LFM) and its active metabolite, teriflunomide (TFM), have drawn a lot of attention for their anticancer activities, treatment of rheumatoid arthritis and malaria due to their capability to inhibit dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. In this investigation, the strength of intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) has been analyzed employing density functional theory (DFT) using B3LYP/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water solution. A detailed electronic structure study has been performed using the quantum theory of atoms in molecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of 76-97 kJ/mol, as a medium hydrogen bond. The effect of substitution on the IHB nature has been studied by natural bond orbital analysis (NBO). 1H NMR calculations show an upward trend in the proton chemical shift of the enolic proton in the chelated ring (14.5 to 15.7ppm) by increasing the IHB strength. All the calculations confirmed the strongest IHB in 5-F-ATFM and the weakest IHB in 2-F-ATFM. Molecular orbital analysis, including the HOMO-LUMO gap and chemical hardness, was performed to compare the reactivity of inhibitors. Finally, molecular docking analysis was carried out to identify the potency of inhibition of these compounds against PfDHODH enzyme.

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Vitamin D Levels Correlate with Metabolic Syndrome Criteria in Algerian Patients: The Ex-vivo Immunomodulatory Effect of α, 25 Dihydroxyvitamin D3

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200402121917 ◽

2020 ◽

Vol 20 (8) ◽

pp. 1282-1294

Author(s):

Meroua Bouchemal ◽

Djennat Hakem ◽

Malha Azzouz ◽

Chafia Touil-Boukoffa ◽

Dalila Mezioug

Keyword(s):

Metabolic Syndrome ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Active Metabolite ◽

Mononuclear Cells ◽

Ex Vivo ◽

No Production ◽

Immunomodulatory Effects ◽

Immune Balance ◽

Vitamin D Levels

Background: Metabolic syndrome (MetS) is a combination of metabolic disorders with increased risks for several diseases, such as cardiovascular diseases and diabetes. It is associated with the presence of various inflammatory molecules. Vitamin D plays an important role in the regulation of metabolism homeostasis. Objective: The main goal of this work is to investigate vitamin D levels among Algerian MetS patients and its possible outcomes on key molecules of the immune response, as well, the immunomodulatory effects of its active metabolite. Methods: We evaluated vitamin D status by the electrochemiluminescence method, Nitric Oxide (NO) levels by the Griess method and Matrix Metalloproteinases (MMPs) activities such as MMP-2 and MMP-9 by zymography in plasma of patients and healthy controls (HC). The immunomodulatory effects of the active metabolite of vitamin D (α-25 (OH)2D3) on the production of NO, IL-6, IL-10, TGF- β and s-CTLA-4 were assessed by Griess method and ELISA, in peripheral blood mononuclear cells (PBMCs) of Algerian MetS patients and HC. MMPs activities were also determined ex-vivo, while iNOS expression was assessed by immunofluorescence staining. Results: Severe vitamin D deficiency was registered in Algerian MetS patients. The deficiency was found to be associated with an elevated in vivo NO production and high MMPs activity. Interestingly, α-25 (OH)2D3 declined the NO/iNOS system and IL-6 production, as well as MMPs activities. However, the ex-vivo production of IL-10, TGF-β increased in response to the treatment. We observed in the same way, the implication of s-CTLA-4 in MetS, which was markedly up-regulated with α-25 (OH)2D3. Conclusion: Our report indicated the relationship between MetS factors and Vitamin D deficiency. The ex-vivo findings emphasize its impact on maintaining regulated immune balance.

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The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)‐Endoxifen in Breast Cancer

Clinical and Translational Science ◽

10.1111/cts.12707 ◽

2019 ◽

Vol 13 (2) ◽

pp. 284-292 ◽

Cited By ~ 2

Author(s):

Jeanine Marie Nardin ◽

Werner Schroth ◽

Thais Abreu Almeida ◽

Thomas Mürdter ◽

Solane Picolotto ◽

...

Keyword(s):

Breast Cancer ◽

Active Metabolite ◽

Plasma Concentrations

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Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

Open Chemistry ◽

10.1515/chem-2020-0046 ◽

2020 ◽

Vol 18 (1) ◽

pp. 681-690

Author(s):

Hassan A. Alhazmi ◽

Adnan A. Kadi ◽

Mohamed W. Attwa ◽

Waquar Ahsan ◽

Manal Mohamed Elhassan Taha ◽

...

Keyword(s):

Cytochrome P450 ◽

Active Metabolite ◽

Dose Adjustment ◽

Internal Standard ◽

Cardiovascular Complications ◽

Antiplatelet Drug ◽

Peak Ratio ◽

Cytochrome P450 Enzymes ◽

Time Intervals ◽

Addictive Substance

AbstractClopidogrel (CLOP) is widely used worldwide for cardiovascular complications. CLOP is highly metabolized in the liver to its active metabolite by cytochrome P450 enzymes. Studies have shown that khat, an addictive substance, is a powerful inhibitor of cytochrome P450 enzymes and can influence the metabolism of drugs that are concomitantly used. Therefore, this study was designed to evaluate the effects of khat on the pharmacokinetics of CLOP in rats. In this study, rats were administered either CLOP alone or CLOP combined with khat and their plasma were obtained at different time intervals and analyzed using the newly developed and validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using foretinib (FTB) as the internal standard. The corresponding peak area of the analyte versus FTB was used for calculating the peak ratio. The validated LC-MS/MS method resulted in the separation of the well-defined quantifiable peaks of CLOP, FTB, and CLOP metabolite within 7 min. Results showed a significant influence of khat on the peak ratio of CLOP metabolite, which was found to be significantly decreased (P < 0.05) in comparison to CLOP alone, suggesting significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.

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Severe Adverse Drug Reactions to Quetiapine in Two Patients Carrying CYP2D6*4 Variants: A Case Report

International Journal of Molecular Sciences ◽

10.3390/ijms22126480 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6480

Author(s):

Céline K. Stäuble ◽

Markus L. Lampert ◽

Thorsten Mikoteit ◽

Martin Hatzinger ◽

Kurt E. Hersberger ◽

...

Keyword(s):

Cytochrome P450 ◽

Case Report ◽

Adverse Drug Reactions ◽

Active Metabolite ◽

Hepatic Metabolism ◽

Cytochrome P450 3A4 ◽

Drug Reactions ◽

Drug Induced ◽

Potential Impact ◽

Intermediate Metabolizer

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.

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OCCURRENCE IN NATURAL PRODUCTS OF A PHYSIOLOGICALLY ACTIVE METABOLITE OF PYRIDOXINE

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)72641-0 ◽

1942 ◽

Vol 143 (2) ◽

pp. 519-530

Author(s):

Esmond E. Snell ◽

Beverly M. Guirard ◽

Roger J. Williams

Keyword(s):

Natural Products ◽

Active Metabolite

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