Inter-individual Variability of In Vivo CYP2D6 Activity in Different Genotypes

AbstractOxidative damage of cells and tissues is broadly implicated in human pathophysiology, including cardiometabolic diseases. Polyphenols, as important constituents of the human diet and potent in vitro free radical scavengers, have been extensively studied for their beneficial effects on cardiometabolic health. However, it has been demonstrated that the in vivo antioxidant activity of polyphenols is distinct from their in vitro free radical-scavenging capacity. Indeed, bioavailability of nutritional polyphenols is low and conditioned by complex mechanisms of absorption, distribution, metabolism and excretion. Nowadays, it is commonly accepted that the cellular antioxidant activity of polyphenols is mainly carried out via modification of transcription of genes involved in antioxidant defence. Importantly, polyphenols also contribute to cardiometabolic health by modulation of a plethora of cellular processes that are not directly associated with antioxidant enzymes, through nutri(epi)genomic mechanisms. Numerous human intervention studies have demonstrated beneficial effects of polyphenols on the key cardiometabolic risk factors. However, inconsistency of the results of some studies led to identification of the inter-individual variability in response to consumption of polyphenols. In perspective, a detailed investigation of the determinants of this inter-individual variability will potentially lead us towards personalised dietary recommendations. The phenomenon of inter-individual variability is also of relevance for supplementation with antioxidant (pro)vitamins.

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OC 8510 BIOTRANSFORMATION OF PRAZIQUANTEL FOR THE PHARMACOKINETIC OPTIMISATION OF PRAZIQUANTEL USE IN MASS DRUG ADMINISTRATION AND DEVELOPMENT OF NEW PAEDIATRIC FORMULATIONS

BMJ Global Health ◽

10.1136/bmjgh-2019-edc.26 ◽

2019 ◽

Vol 4 (Suppl 3) ◽

pp. A11.1-A11

Author(s):

Roslyn S Thelingwani ◽

Nyasha Kapungu ◽

Xueqing Li ◽

Comfort Kanji ◽

Chenai Mutiti ◽

...

Keyword(s):

Drug Administration ◽

Mass Drug Administration ◽

Liver Microsomes ◽

Individual Variability ◽

Clinical Samples ◽

Pharmacokinetic Data ◽

Detailed Knowledge ◽

Pbpk Modelling

BackgroundPraziquantel (PZQ) is the only drug available for the treatment of all forms of schistosomiasis. New paediatric formulations for the active enantiomer R-PZQ and the racemate PZQ are currently under development. There is however limited drug metabolism and pharmacokinetic data on PZQ available to support these initiatives. Detailed knowledge of PZQ metabolism will enable the use of PBPK modelling to determine appropriate doses for the new formulations in paediatric patients and to predict risks for drug-drug interactions in mass drug administration.MethodsBiotransformation studies on PZQ were conducted in human liver microsomes and recombinant Cytochrome P450s (CYPs). Structure elucidation was inferred from mass spectra. Enzyme kinetic studies to determine the Michaelis-Menten kinetics, Km and Vmax, of the formation of the main metabolites and analysis of clinical samples were determined by LC-MS/MS.ResultsCYP reaction phenotyping studies with HLM and r-CYPs indicate major involvement of CYP1A2, 2 C19, 2D6 and 3A4/5 in the metabolism of R- and S-PZQ. Biotransformation studies showed that PZQ is metabolised to cis-4-OH-PZQ mainly by CYP1A2 and CYP2C19. CYP3A4/5 metabolises PZQ to a mono-hydroxyl metabolite (X-OH-PZQ) whilst CYP2D6 metabolises PZQ to minor novel mono-hydroxyl metabolite (Y-OH-PZQ) both pending structural elucidation by nuclear magnetic resonance. R-PZQ was more rapidly cleared than S–PZQ with variable interindividual AUC and Cmax.Discussion and conclusionThe differential role of CYP1A2 and CYP2C19 and of CYP3A4 and CYP3A5 in the formation the 4-OH-PZQ and the novel X-OH-PZQ respectively are intriguing findings as this has not been reported before in humans. In vitro, cis and not trans 4-OH-PZQ formation has been observed contrary in vivo reports in humans which indicate trans 4-OH-PZQ as the main metabolite. The data will enable us to understand the rapid clearance of PZQ and predict potential drug-drug-gene interactions which mayexplain the inter-individual variability of PZQ pharmacokinetics.

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Phase I and pharmacokinetic (PK) dose-adjusted study of IV vinflunine (VFL) in cancer patients with liver dysfunction (LD): Pharmacokinetic results

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.2523 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 2523-2523

Author(s):

B. Paule ◽

F. Saliba ◽

M. Gil-Delgado ◽

C. Puozzo ◽

S. Favrel ◽

...

Keyword(s):

Phase I ◽

Antitumour Activity ◽

Vinca Alkaloid ◽

Individual Variability ◽

Pharmacokinetic Parameters ◽

Control Group ◽

Microtubule Inhibitor ◽

Blood Concentrations ◽

Significant Difference

2523 Background: VFL is a novel microtubule inhibitor of the vinca alkaloid class that has shown high antitumour activity in several in vivo tumour models and in clinical trials. VFL is mainly eliminated through metabolism and bile excretion. Therefore this trial was designed to determine if LD could increase exposure and toxicity of VFL and require a dose-adjustment. Methods: This trial had a sequential design with the objective of determining the maximal tolerated dose (MTD) and the recommended dose (RD) in three groups of LD based on clinical and biological criteria: mild (PT > 70% and UNL < serum bilirubin = 1.5xUNL), moderate (Child-Pugh A) and severe (Child-Pugh B). VFL and 4-O-deacetylvinflunine (DVFL), its only active metabolite, were quantified in whole blood during cycle 1. PK parameters (AUCinf, Cltot) were estimated using a non-compartmental analysis and were compared using a one-way ANOVA with group factor either between groups or between groups and a control group of 49 patients without LD enrolled in phase I trials). Results: Three VFL doses were investigated: The inter-individual variability (CV) in AUCinf was approximately 30% for all groups. Even if AUCinf increased between mild and moderate groups, no difference was demonstrated between moderate and severe LD groups. All individual values were within the range of control values. Cltot were also similar between groups and the control group. Statistical analysis did not evidence any significant difference between groups. No difference was observed in blood concentrations of DVFL compared to the control group. No relationship between dose limiting toxicity and blood exposure was evidenced. Conclusions: The results showed that vinflunine and DVFL pharmacokinetic parameters do not appear to be affected by the degree of LD. However, the dose of VFL has to be adjusted to the level of LD for safety reasons. [Table: see text] No significant financial relationships to disclose.

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In vivo intra- and inter-individual variability study of human stratum corneum by confocal Raman spectroscopy

Vibrational Spectroscopy ◽

10.1016/j.vibspec.2016.10.007 ◽

2016 ◽

Vol 87 ◽

pp. 199-206

Author(s):

Laurita dos Santos ◽

Joao Lucas Rangel ◽

Vamshi Krishna Tippavajhala ◽

Michely Glenda Pereira da Silva ◽

Borys Mogilevych ◽

...

Keyword(s):

Raman Spectroscopy ◽

Stratum Corneum ◽

Individual Variability ◽

Confocal Raman Spectroscopy ◽

Human Stratum Corneum ◽

Confocal Raman ◽

Variability Study

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The Place of PET to Assess New Therapeutic Effectiveness in Neurodegenerative Diseases

Contrast Media & Molecular Imaging ◽

10.1155/2018/7043578 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Anne-Claire Dupont ◽

Bérenger Largeau ◽

Denis Guilloteau ◽

Maria Joao Santiago Ribeiro ◽

Nicolas Arlicot

Keyword(s):

Neurodegenerative Diseases ◽

Pet Imaging ◽

Molecular Mechanisms ◽

Individual Variability ◽

Response To Therapy ◽

Therapeutic Effectiveness ◽

Imaging Method ◽

Detection And Identification ◽

Positron Emission

In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. We also discuss opportunities for PET imaging to drive more personalized neuroprotective and therapeutic strategies, taking into account individual variability, within the growing framework of precision medicine.

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A new statistical method to analyze Morris Water Maze data using Dirichlet distribution

F1000Research ◽

10.12688/f1000research.20072.2 ◽

2019 ◽

Vol 8 ◽

pp. 1601

Author(s):

Marianne Maugard ◽

Cyrille Doux ◽

Gilles Bonvento

Keyword(s):

Morris Water Maze ◽

Water Maze ◽

Dirichlet Distribution ◽

Statistical Tests ◽

Individual Variability ◽

Mean Values ◽

Normal Distributions ◽

Memory Impairments ◽

The Common

The Morris Water Maze (MWM) is a behavioral test widely used in the field of neuroscience to evaluate spatial learning memory of rodents. However, the interpretation of results is often impaired by the common use of statistical tests based on independence and normal distributions that do not reflect basic properties of the test data, such as the constant-sum constraint. In this work, we propose to analyze MWM data with the Dirichlet distribution, which describes constant-sum data with minimal hypotheses, and we introduce a statistical test based on uniformity (equal amount of time spent in each quadrant of the maze) that evaluates memory impairments. We demonstrate that this test better represents MWM data and show its efficiency on simulated as well as in vivo data. Based on Dirichlet distribution, we also propose a new way to plot MWM data, showing mean values and inter-individual variability at the same time, on an easily interpretable chart. Finally, we conclude with a perspective on using Bayesian analysis for MWM data.

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The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

Current Drug Metabolism ◽

10.2174/1389200219666180821094502 ◽

2019 ◽

Vol 20 (2) ◽

pp. 91-102 ◽

Cited By ~ 22

Author(s):

Li Di

Keyword(s):

Tissue Distribution ◽

Critical Role ◽

Individual Variability ◽

Human Pharmacokinetics ◽

Metabolizing Enzymes ◽

Soft Drugs ◽

Hydrolysis Of Esters ◽

The Impact

Background:Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, as well as bioconverting prodrugs and soft drugs. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. Marked species differences in CES tissue distribution and catalytic activity are particularly challenging in human translation.Methods:Review and summarization of CES fundamentals and applications in drug discovery and development.Results:Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Monkeys appear to be more predictive of human pharmacokinetics for CES substrates than other species. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines.Conclusion:Although significant advances have been made in our understanding of CESs, in vitro - in vivo extrapolation of clearance is still in its infancy and further exploration is needed. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.

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In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma

European Journal of Clinical Pharmacology ◽

10.1007/s002280000218 ◽

2000 ◽

Vol 56 (9-10) ◽

pp. 651-657 ◽

Cited By ~ 26

Author(s):

J. Chládek ◽

G. Zimová ◽

M. Beránek ◽

J. Martínková

Keyword(s):

Cyp2d6 Activity ◽

Activity Comparison

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Lycopene isomerisation takes place within enterocytes during absorption in human subjects

British Journal Of Nutrition ◽

10.1017/s0007114510000103 ◽

2010 ◽

Vol 103 (12) ◽

pp. 1800-1807 ◽

Cited By ~ 42

Author(s):

Myriam Richelle ◽

Belén Sanchez ◽

Isabelle Tavazzi ◽

Pierre Lambelet ◽

Karlheinz Bortlik ◽

...

Keyword(s):

Fruits And Vegetables ◽

Mixed Micelles ◽

Human Subjects ◽

Individual Variability ◽

Intestinal Cell ◽

Considerable Proportion ◽

Cell Clones ◽

Complex Process

Lycopene in fruits and vegetables occurs mostly (80–97 %) in the all-E configuration, whereas a considerable proportion of lycopene in the human body is present as Z-isomers. The Z-isomers offer potentially better health benefits and show improved antioxidant activity in vitro when compared with the all-E-isomer. The absorption of dietary lycopene is a complex process involving transfer of the carotenoid from the food matrix into micelles, uptake by enterocytes, packaging into chylomicrons and finally secretion into plasma. Isomerisation could take place at any of these individual steps. By exploiting in vitro and in vivo models, we traced lycopene isomerisation during absorption using various methods to mimic gastric and duodenal conditions, incorporation into mixed micelles, absorption and metabolism by various Caco-2 cell clones, and performed a postprandial study in human subjects to identify the profile of lycopene isomers in plasma chylomicrons. We demonstrate that all-E-lycopene remains unchanged during its passage in the gastrointestinal tract, including its incorporation into mixed micelles. The key site of lycopene isomerisation is inside the intestinal cells resulting in 29 % of lycopene as Z-isomers. Lycopene isomerisation in the various Caco-2 cell clones is consistent with that observed in human chylomicrons formed in a postprandial state. There is no selection in the release of lycopene isomers from enterocytes. Although there is a huge inter-individual variability of total lycopene absorption reported both in in vitro intestinal cell lines as well as in human chylomicrons, the lycopene isomer profile is quite similar.

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