248 research outputs found
Human variability in kinetics for the major metabolic pathways : Application to chemical risk assessment
No full textThis thesis deals with the statistical analysis of human variability in kinetics for the major metabolic pathways (Phase I (CYP isoforms (CYP1A2, CYP2C9, CYP2C19 CYP2D6, CYP2E1, CYP3A4), hydrolysis, Alcohol dehydrogenase). Phase n (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion) to investigate the appropriateness of the default uncertainty factor (10°^ 3.16) currently in use for the risk assessment of thresholded toxicants and accounting for human variability in kinetics. Probe substrates were selected on the basis that oral absorption was total and that the metabolic route was the primary route of elimination of the compound (60-100% of an oral). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population (effect of ethnicity, age and disease) using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve (AUG)) and acute exposure (Cmax). All parameters were analysed using the assumptions that data were either normally or log normally distributed and that kinetics were linear. Three sets of pathway-related uncertainty factors were calculated using the lognormal variability in kinetics to cover 95^, 97.5^ and 99"^ centile of the general healthy adult population respectively. These pathway-related uncertainty factors were also calculated for subgroups using the magnitude of the difference in internal dose between each subgroup and healthy adults (ratio of geometric means and the subgroup specific variability). Low inter-individual variability (about 21-31%) and pathway-related uncertainty factors (1.6- 2.2, 99*^ centile) were found for all monomorphic pathways with the exception of CYP3A4 metabolism for which variability after oral dosing was 46% (2.8, 99"^ centile). Polymorphic pathways showed that the current kinetic default would not be adequate to cover healthy adult poor metabolisers for CYP2D6 and CYP2C19 metabolism and slow acetylators for N-acetylation and uncertainty factors of 26, 52 and 5.2 would cover these</p
The Effect of Lighting on Performance of Tasks Requiring Near Vision in Older Adults
No full textAbstract
Date Presented 4/1/2017
The study examined the impact of lighting on occupational task performance in older adults and the effect of lighting on perceived effort during task performance. Results suggest lighting may affect performance and perceived effort in older adults performing tasks requiring near vision.
Primary Author and Speaker: Karen James
Contributing Authors: Max Ito, Rachelle Dorne, JoAnne Wright</jats:p
Polymorphic CYP2C19 and N-acetylation: human variability in kinetics and pathway-related uncertainty factors
No full textCYP2C19-mediated oxidation and N-acetylation constitute major phase I and phase II polymorphic pathways of xenobiotic metabolism in humans. Analysis of human variability in kinetics for these pathways has been carried out for compounds metabolised extensively (>60%) by these routes. Data for minor substrates for CYP2C19 metabolism (10–60%) have also been analysed. Published pharmacokinetic studies (after oral and intravenous dosing) in CYP2C19 non-phenotyped healthy adults (NPs), and phenotyped extensive (EMs), slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration–time curve) and primarily to acute exposure (peak concentration). Similar analyses were performed for the N-acetylation pathway using data for fast acetylators (FA) and slow acetylators (SA). Interindividual variability in the kinetics of CYP2C19 substrates after oral dosage was greater in EMs than in NPs (60 vs 43% for clearances and 54 vs 45% for Cmax). Lower variability was found for N-acetylation for both phenotypes (32 and 22% for FA and SA, respectively). The internal dose of CYP2C19 substrates in PM subjects would be 31-fold higher than in EMs, while for N-acetylated substrates there was a three-fold difference between SA and FA subjects. Pathway-related uncertainty factors were above the default safety factor of 3.16 for most subgroups and values of 52 and 5.2 would be necessary to cover to the 99th centile of the poor metaboliser phenotype for CYP2C19 and N-acetylation, respectively. An exponential relationship (R²=0.86) was found between the extent of CYP2C19 metabolism and the difference in internal dose between EMs and PMs. The kinetic default factor (3.16) would cover PMs for substrates for which CYP2C19 was responsible for up to 20–30% of the metabolism in EMs
Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation)
No full textHuman variability in the kinetics of a number of phase I (CYP2A6, CYP2C9, CYP2E1, alcohol dehydrogenase and hydrolysis) and phase II enzymes (glycine and sulphate conjugation) was analysed using probe substrates metabolised extensively (>60%) by these routes. Published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and available data on subgroups of the population (effects of ethnicity, age and disease) were abstracted using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual differences in kinetics for all these pathways were low in healthy adults ranging from 21 to 34%. Pathway-related uncertainty factors to cover the 95th, 97.5th and 99th centiles of healthy adults were derived for each metabolic route and were all below the 3.16 kinetic default uncertainty factor in healthy adults, with the possible exception of CYP2C9*3/*3 poor metabolisers (based on a very limited number of subjects). Previous analyses of other pathways have shown that neonates represent the most susceptible subgroup and this was true also for glycine conjugation for which an uncertainty factor of 29 would be required to cover 99% of this subgroup. Neonatal data were not available for any other pathway analysed.Abbreviations: CYP Cytochrome P450, AUC Area under the plasma-concentration-time-curve, Cmax Maximum plasma concentratio
The refinement of uncertainty/safety factors in risk assessment by the incorporation of data on toxicokinetic variability in humans
No full textThe derivation of safe levels of exposure in humans for compounds that are assumed to cause threshold toxicity has relied on the application of a 100-fold uncertainty factor to a measure for the threshold, such as the no observed adverse effect level (NOAEL) or the benchmark dose (BMD). This 100-fold safety factor consists of the product of two 10-fold factors allowing for human variability and interspecies differences. The International Programme on Chemical Safety has suggested the subdivision of these 10-fold factors to allow for variability in toxicokinetics and toxicodynamics. This subdivision allows the replacement of the default uncertainty factors with a chemical-specific adjustment factor (CSAF) when suitable data are available. This short review describes potential options to refine safety factors used in risk assessment, with particular emphasis on pathway-related uncertainty factors associated with variability in kinetics. These pathway-related factors were derived from a database that quantified interspecies differences and human variability in phase I metabolism, phase II metabolism, and renal excretion. This approach allows metabolism and pharmacokinetic data in healthy adults and subgroups of the population to be incorporated in the risk-assessment process and constitutes an intermediate approach between simple default factors and chemical-specific adjustment factors
Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review
No full textThis review provides an account of recent developments arising from a database that defined human variability in phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion. This database was used to derive pathway-related uncertainty factors for chemical risk assessment that allow for human variability in toxicokinetics. Probe substrates for each pathway of elimination were selected on the basis that oral absorption was >95% and that the metabolic route was the primary route of elimination of the compound (60–100% of a dose). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration–time curve (AUC) and acute exposure (Cmax) (data not presented here). The pathway-related uncertainty factors were calculated to cover 95%, 97.5% and 99% of the population of healthy adults and of each subgroup.Pathway-related uncertainty factors allow metabolism data to be incorporated into the derivation of health-based guidance values. They constitute an intermediate approach between the general kinetic default factors (3.16) and a chemical-specific adjustment factor. Applications of pathway-related uncertainty factors for chemical risk assessment and future refinements of the approach are discussed. A knowledge-based framework to predict human variability in kinetics for xenobiotics showing a threshold dose below which toxic effects are not observed, is proposed to move away from default assumptions. <br/
Investigating the interaction between organic anion transporter 1 and ochratoxin A: An in silico structural study to depict early molecular events of substrate recruitment and the impact of single point mutations
Get PDFOrganic anion transporters (OATs) belong to a subgroup of the solute carrier 22 transporter family. OATs have a central role in xenobiotic disposition affecting the toxicokinetics of its substrates and inter-individual differences in their expression, activity and function impact both toxicokinetics and toxicodynamics. Amongst OATs, OAT1 (solute carrier family 22 member 6) is involved in the urinary excretion of many xenobiotics bringing substrates into renal proximal tubular cells which can then be secreted across the apical membrane into the tubule lumen. The mycotoxin ochratoxin A has been shown to have a high affinity for OAT1, which is an important renal transporter involved in its urinary excretion. Nowadays, molecular modeling techniques are widely applied to assess protein-ligand interactions and may provide a tool to depict the mechanic of xenobiotic action be it toxicokinetics or toxicodynamics. This work provides a structured pipeline consisting of docking and molecular dynamic simulations to study OAT1-ligand interactions and the impact of OAT1 polymorphisms on such interactions. Such a computational structure-based analytical framework allowed to: i) model OAT1-substrate complex formation and depict the features correlating its sequence, structure and its capability to recruit substrates; and ii) investigate the impact of OAT1 missense mutations on substrate recruitment. Perspectives on applying such a structured pipeline to xenobiotic-metabolising enzymes are discussed
A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species
No full textSafrole, a 162.2 Da natural compound belonging to the alkenylbenzenes class, is classified as a possible carcinogen to humans by IARC (group IIB) and has proven to be genotoxic and carcinogenic to rodents. Despite its use as a food or feed additive, it is forbidden in many countries due to its documented toxicity; yet, it is still broadly present within food and feed and is particularly abundant in spices, herbs and essential oils. Specifically, safrole may exert its toxicity upon bioactivation to its proximate carcinogen 1′-hydroxy-safrole via specific members of the cytochrome P450 protein family with a certain inter/intra-species variability. To investigate this variability, an in-silico workflow based on molecular modelling, docking and molecular dynamics has been successfully applied. This work highlighted the mechanistic basis underpinning differences among humans, cats, chickens, goats, sheep, dogs, mice, pigs, rats and rabbits. The chosen metric to estimate the likeliness of formation of 1′-hydroxy-safrole by the species-specific cytochrome P450 under investigation allowed for the provision of a knowledge-based ground to rationally design and prioritise further experiments and deepen the current understanding of alkenylbenzenes bioactivation and CYPs mechanics. Both are crucial for a more informed framework of analysis for safrole toxicity
Programma Quo Suo Ac Inclyti Iuridici Ordinis Nomine, Ad Dissertationem Solennem Iuridicam ... Dn. Herman Hinr. von Dorne ... De Inobedientia Impuni Von Unstraffbahren Ungehorsam Die VII. Octobris. MDCC. ... Invitat. Johannes Klein ...
Get PDFPreventing the Interaction between Coronaviruses Spike Protein and Angiotensin I Converting Enzyme 2: An In Silico Mechanistic Case Study on Emodin as a Potential Model Compound
Get PDFEmodin, a widespread natural anthraquinone, has many biological activities including health-protective and adverse effects. Amongst beneficial effects, potential antiviral activity against coronavirus responsible for the severe acute respiratory syndrome outbreak in 2002–2003 has been described associated with the inhibition of the host cells target receptors recognition by the viral Spike protein. However, the inhibition mechanisms have not been fully characterized, hindering the rational use of emodin as a model compound to develop more effective analogues. This work investigates emodin interaction with the Spike protein to provide a mechanistic explanation of such inhibition. A 3D molecular modeling approach consisting of docking simulations, pharmacophoric analysis and molecular dynamics was used. The plausible mechanism is described as an interaction of emodin at the protein–protein interface which destabilizes the viral protein-target receptor complex. This analysis has been extended to the Spike protein of the coronavirus responsible for the current pandemic hypothesizing emodin’s functional conservation. This solid knowledge-based foothold provides a possible mechanistic rationale of the antiviral activity of emodin as a future basis for the potential development of efficient antiviral cognate compounds. Data gaps and future work on emodin-related adverse effects in parallel to its antiviral pharmacology are explored
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