Evaluation of the pharmacokinetics, chylomicron inhibition, and toxicity of colchicine in rats given low doses.

Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited high total body clearance and volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.

Steps towards operationalizing One Health approaches.

One Health recognizes the health of humans, agriculture, wildlife, and the environment are interrelated. The concept has been embraced by international health and environmental authorities such as WHO, WOAH, FAO, and UNEP, but One Health approaches have been more practiced by researchers than national or international authorities. To identify priorities for operationalizing One Health beyond research contexts, we conducted 41 semi-structured interviews with professionals across One Health sectors (public health, environment, agriculture, wildlife) and institutional contexts, who focus on national-scale and international applications. We identify important challenges, solutions, and priorities for delivering the One Health agenda through government action. Participants said One Health has made progress with motivating stakeholders to attempt One Health approaches, but achieving implementation needs more guidance (action plans for how to leverage or change current government infrastructure to accommodate cross-sector policy and strategic mission planning) and facilitation (behavioral change, dedicated personnel, new training model).

Exploring various measures of the area under the curve for the assessment of dose-proportionality and estimation of bioavailability.

OBJECTIVE: In pharmacokinetics, the area under the concentration versus time curve (AUC) extrapolated to infinity (AUC0-∞) is the preferred metric but it is not always possible to have a reliable estimate of the terminal phase half-life. Here we sought to explore the accuracy of three different area measures to accurately identify dose proportionality and bioavailability. METHODS: One to three compartment model simulations with different doses for dose-proportionality or different rates and/or extents of bioavailability. Area measures evaluated were AUC0-∞, to the last quantifiable concentration (AUCtlast), and to a common time value (AUCt'). RESULTS: Under linear pharmacokinetics, AUCt' provided the most accurate measure of dose proportionality. Except for the one compartment model where AUC0-∞ provided the best predictor of the true measure, there was no clear advantage to the use of either of the three measures of AUC. CONCLUSION: With uncertainty about the terminal phase half-life, the use of AUCt' can be a very useful and even the preferred measure of exposure for use in assessing proportionality in exposure between doses. The choice of AUC measure in bioavailability is less clear and may depend on compartmental nature of the drug, and study parameters including assay sensitivity and sampling protocols.

Effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation on offspring outcomes: a systematic review of the evidence.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation. Methods: We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion. Results: We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available. Conclusion/interpretation: We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies. Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.

Pharmacokinetics of cycloheximide in rats and evaluation of its effect as a blocker of intestinal lymph formation.

Cycloheximide (CHX) has been used to reduce the flow of intestinal lymph and as a non-surgical tool to study drug absorption via the intestinal lymphatics. Pharmacokinetic information on the agent, and its relationship to effect and toxicity, have not been examined. The goal of this study was to provide pharmacokinetic data and link it to lymph-blocking and toxicological effects. Jugular-vein cannulated (JVC) adult Sprague-Dawley male rats were administered 0.5 mg/kg CHX by oral, intraperitoneal (ip), and intravenous routes followed by blood draws, and CHX was assayed using LC-MS/MS. Another four JVC rats were given peanut oil (2 mL/kg) without and then with CHX to measure effects on lipid absorption as a surrogate indicator of lymph flow. One-week later plasma biochemistry measures were obtained. The results indicated that CHX had a high clearance and volume of distribution, and oral absolute bioavailability of 0.47 with 0.5 mg/kg. CHX was associated with dose- and route-dependent pharmacokinetics. The relative bioavailability after ip doses was over 3. CHX had low plasma protein binding and minor urinary excretion. Metabolism appeared to be occur by oxidation and glucuronidation. Reductions in plasma lipids (24-40 %) were seen after 2.5 mg/kg orally with signs of inflammation and increased liver enzymes persisting for a week after the dose. CHX was associated with a reduction in lipid absorption after oral doses of 2.5 mg/kg, which seems to justify its use as a non-surgical tool to evaluate the lymphatic pathway of absorption of drugs. However, it also possesses hepatotoxicity, which should be taken into consideration in its use.

Use of a common spreadsheet program to demonstrate the ability of Bayesian forecasting to estimate the pharmacokinetic parameters of antibiotics.

OBJECTIVES: Recent guidelines for vancomycin have incorporated the use of Bayesian forecasting, reinforcing the need to inform students in pharmacy and clinical pharmacology of its use in therapeutic drug monitoring. The goal was to devise a PharmD research project that could demonstrate to students through simulation and data generation the utility of the Bayesian approach in estimating the pharmacokinetics of gentamicin and vancomycin. METHODS: A series of steps were devised using Microsoft Excel to simulate patient data based on study-derived means and variances, pharmacokinetic modelling, random selection of sparse blood samples, introduce random error into the selected concentrations based on assay variability measure, and finally, inputting of the information into an add-in computer program to find the pharmacokinetic estimates using Bayesian forecasting. KEY FINDINGS: Excellent correlations were seen between Bayesian estimates and true clearances. Lower assay variability tended to provide better estimates than larger assay variability for gentamicin, and for vancomycin, selecting a sample during the distribution phase and near the trough values tended to provide estimates with less bias and greater precision. CONCLUSIONS: The approach used was able to demonstrate all aspects involved in Bayesian forecasting, and the results supported its use for these antibiotics.

16R-HETE and 16S-HETE alter human cytochrome P450 1B1 enzyme activity probably through an allosteric mechanism.

Cytochrome P450 1B1 (CYP1B1) has been widely associated with the development of cardiac pathologies due to its ability to produce cardiotoxic metabolites like midchain hydroxyeicosatetraenoic acids (HETEs) from arachidonic acid (AA) through an allylic oxidation reaction. 16-HETE is a subterminal HETE that is also produced by CYP-mediated AA metabolism. 19-HETE is another subterminal HETE that was found to inhibit CYP1B1 activity, lower midchain HETEs, and have cardioprotective effects. However, the effect of 16-HETE enantiomers on CYP1B1 has not yet been investigated. We hypothesized that 16(R/S)-HETE could alter the activity of CYP1B1 and other CYP enzymes. Therefore, this study was carried out to investigate the modulatory effect of 16-HETE enantiomers on CYP1B1 enzyme activity, and to examine the mechanisms by which they exert these modulatory effects. To investigate whether these effects are specific to CYP1B1, we also investigated 16-HETE modulatory effects on CYP1A2. Our results showed that 16-HETE enantiomers significantly increased CYP1B1 activity in RL-14 cells, recombinant human CYP1B1, and human liver microsomes, as seen by the significant increase in 7-ethoxyresorufin deethylation rate. On the contrary, 16-HETE enantiomers significantly inhibited CYP1A2 catalytic activity mediated by the recombinant human CYP1A2 and human liver microsomes. 16R-HETE showed stronger effects than 16S-HETE. The sigmoidal binding mode of the enzyme kinetics data demonstrated that CYP1B1 activation and CYP1A2 inhibition occurred through allosteric regulation. In conclusion, our study provides the first evidence that 16R-HETE and 16S-HETE increase CYP1B1 catalytic activity through an allosteric mechanism.

Laminar flow-based microfluidic systems for molecular interaction analysis-Part 2: Data extraction, processing and analysis.

The rate at which fluorescently-labeled biomolecules, that are flowing at a constant speed in a microfluidic channel, diffuse into an adjacent buffer stream can be used to calculate the diffusion coefficient of the molecule, which then gives a measure of its size. Experimentally, determining the rate of diffusion involves capturing concentration gradients in fluorescence microscopy images at different distances along the length of the microfluidic channel, where distance corresponds to residence time, based on the flow velocity. The preceding chapter in this journal covered the development of the experimental setup, including information about the microscope camera detection systems used to acquire fluorescence microscopy data. In order to calculate diffusion coefficients from fluorescence microscopy images, intensity data are extracted from the images and then appropriate methods of processing and analyzing the data, including the mathematical models used for fitting, are applied to the extracted data. This chapter begins with a brief overview of digital imaging and analysis principles, before introducing custom software for extracting the intensity data from the fluorescence microscopy images. Subsequently, methods and explanations for performing the necessary corrections and appropriate scaling of the data are provided. Finally, the mathematics of one-dimensional molecular diffusion is described, and analytical approaches to obtaining the diffusion coefficient from the fluorescence intensity profiles are discussed and compared.

Laminar flow-based microfluidic systems for molecular interaction analysis-Part 1: Chip development, system operation and measurement setup.

The recent advent of laminar flow-based microfluidic systems for molecular interaction analysis has enabled transformative new profiling of proteins in regards to their structure, disordering, complex formation and interactions in general. Based on the diffusive transport of molecules perpendicular to the direction of laminar flow in a microfluidic channel, systems of this type promise continuous-flow, high-throughput screening of complex, multi-molecule interactions, while remaining tolerant to heterogeneous mixtures. Using common microfluidic device processing, the technology provides unique opportunities, as well as device design and experimental challenges, for integrative sample handling approaches that can investigate biomolecular interaction events in complex samples with readily available laboratory equipment. In this first chapter of a two-part series, we introduce system design and experimental setup requirements for a typical laminar flow-based microfluidic system for molecular interaction analysis in the form of what we call the 'LaMInA system' (Laminar flow-based Molecular Interaction Analysis system). We provide microfluidic device development advice on choice of device material, device design, including impact of channel geometry on the signal acquisition, and on design limitations and possible post-fabrication treatments to redress these. Finally. we cover aspects of fluidic actuation, such as selecting, measuring and controlling the flow rate appropriately, and provide a guide to possible fluorescent labels for proteins, as well as options for the fluorescence detection hardware, all in the context of assisting the reader in developing their own laminar flow-based experimental setup for biomolecular interaction analysis.

The enantioselective separation and quantitation of the hydroxy-metabolites of arachidonic acid by liquid chromatography - tandem mass spectrometry.

Arachidonic acid (AA) is a polyunsaturated fatty acid with a structure of 20:4(ω-6). Cytochrome P450s (CYPs) metabolize AA to several regioisomers and enantiomers of hydroxyeicosatetraenoic acids (HETEs). The hydroxy-metabolites (HETEs) exist as enantiomers in the biological system. The chiral assays developed for HETEs are so far limited to a few assays reported for midchain HETEs. The developed method is capable of quantitative analysis for midchain, subterminal HETE enantiomers, and terminal HETEs in microsomes. The peak area or height ratios were linear over concentrations ranging (0.01 -0.6 µg/ml) with r2 > 0.99. The intra-run percent error and coefficient of variation (CV) were ≤ ± 12 %. The inter-run percent error and coefficient of variation (CV)were ≤ ± 13 %, and ≤ 15 %, respectively. The matrix effect for the assay was also within the acceptable limit (≤ ± 15 %). The recovery of HETE metabolites ranged from 70 % to 115 %. The method showed a reliable and robust performance for chiral analysis of cytochrome P450-mediated HETE metabolites.

Calculating incidence of Influenza-like and COVID-like symptoms from Flutracking participatory survey data.

This article describes a new method for estimating weekly incidence (new onset) of symptoms consistent with Influenza and COVID-19, using data from the Flutracking survey. The method mitigates some of the known self-selection and symptom-reporting biases present in existing approaches to this type of participatory longitudinal survey data. The key novel steps in the analysis are: 1) Identifying new onset of symptoms for three different Symptom Groupings: COVID-like illness (CLI1+, CLI2+), and Influenza-like illness (ILI), for responses reported in the Flutracking survey. 2) Adjusting for symptom reporting bias by restricting the analysis to a sub-set of responses from those participants who have consistently responded for a number of weeks prior to the analysis week. 3) Weighting responses by age to adjust for self-selection bias in order to account for the under- and over-representation of different age groups amongst the survey participants. This uses the survey package [22] in R [30]. 4) Constructing 95% point-wise confidence bands for incidence estimates using weighted logistic regression from the survey package [21] in R [28]. In addition to describing these steps, the article demonstrates an application of this method to Flutracking data for the 12 months from 27th April 2020 until 25th April 2021.

Analysis of cycloheximide in rat specimens using liquid chromatography with tandem massspectrometry detection.

The development of a selective and sensitive high-performance liquid chromatographic tandem mass spectrometric method for the determination of cycloheximide (CHX) in rat blood and plasma is described. The extraction of CHX and colchicine as internal standard from blood fluid (0.1 mL) was achieved using n-hexane: dichloromethane: isopropanol (20:10:1 v/v/v). The mobile phase, a combination of methanol:10 mM ammonium acetate (85:15, v/v), was pumped at 0.2 mL/min through a C18 analytical column with a run time of 3.5 min. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring (MRM) mode. The assay exhibited excellent linearity (r2 > 0.999) in peak area response over the concentration ranges of 2-1000 ng CHX /mL blood fluid. The mean absolute recoveries for 20, 100 and 500 ng/mL CHX in blood fluid using the present extraction procedure were > 97%. The intra- and inter-day coefficients of variation in the plasma and blood and mean error were < 13% at different concentrations. Samples had limited stability at room temperature, and speedy processing is needed. After intravenous administration, rats had measurable concentrations of CHX for up to 24 h after dosing with 1 mg/kg of cycloheximide. The method displayed a high caliber of sensitivity and selectivity for detecting very low concentrations of CHX in rats.

Structure of the Region-Technology Network as a Driver for Technological Innovation.

Agglomeration and spillovers are key phenomena of technological innovation, driving regional economic growth. Here, we investigate these phenomena through technological outputs of over 4,000 regions spanning 42 countries, by analyzing more than 30 years of patent data (approximately 2.7 million patents) from the European Patent Office. We construct a bipartite network-based on revealed comparative advantage-linking geographic regions with areas of technology and compare its properties to those of artificial networks using a series of randomization strategies, to uncover the patterns of regional diversity and technological ubiquity. Our results show that the technological outputs of regions create nested patterns similar to those of ecological networks. These patterns suggest that regions need to dominate various technologies first (those allegedly less sophisticated), creating a diverse knowledge base, before subsequently developing less ubiquitous (and perhaps more sophisticated) technologies as a consequence of complementary knowledge that facilitates innovation. Finally, we create a map-the Patent Space Network-showing the interactions between technologies according to their regional presence. This network reveals how technology across industries co-appear to form several explicit clusters, which may aid future works on predicting technological innovation due to agglomeration and spillovers.

Does a sudden shift of testing format from closed-book to open-book change the characteristics of test scores on summative final exams?

INTRODUCTION: In response to the COVID-19 pandemic, most universities in North America transitioned to online instruction and assessment in March 2020. Undergraduate pharmacy students in years one to three of two four-year entry-to-practice programs at a university in Canada were administered open-book examinations to complete their didactic winter-term courses in pharmaceutical sciences; behavioural, social, and administrative sciences; and pharmacotherapeutics. The impacts of the switch to open-book examinations on final exam characteristics are examined. METHODS: The ratios and correlations of final exam and midterm grades in 2020, where final exams were open-book, and in 2019, where finals were closed-book, were calculated and compared. RESULTS: In 2020, the ratio of final exam to midterm exam scores for five out of seven courses were significantly larger than they were in 2019. Alternatively, for all but one course, the correlations between midterm and final examination grades showed no significant difference from 2019 to 2020. CONCLUSIONS: Compared to 2019 when finals were administered in a closed-book format, a sudden shift to an open-book format for final exams in 2020 appears to be associated with the final exams becoming easier relative to midterms. However, when considering how final and midterm exam grades correlate year over year, in all but one class, there was no significant difference. These findings suggest that changing exams to be open-book may change how they can be used to inform criterion-referenced or absolute grading decisions but not norm-referenced or rank-based decisions.

Online interviews for the selection of applicants for admission into an entry to practice program in pharmacy: Relationship to performance and student perspectives.

INTRODUCTION: Admissions processes for entry-to-practice pharmacy programs across North America vary in the types of information used to decide which students to admit. The use of online interviews emerged at our program as an option to assess basic communication skills and personal traits to supplement traditional achievement measures such as prerequisite course grade point average (GPA) and admissions letters. METHODS: Student cumulative grade, year-by-year grade, and some grades from selected classes were correlated with the interview score for three years of consecutive cohorts. Linear regression was used to explore relationships. A survey was completed by students to understand their views on the use of the online interview process. RESULTS: There was no relationship seen between the compiled GPA and the interview score. The survey data revealed a strong preference for online compared to face-to-face interviews, with high student agreement that the interviews provide a good opportunity to demonstrate general communication skills. An assessment of the strength of the relationships of interview scores with a set of program GPA outcomes showed limited predictive utility. Scores weakly correlated with performance in communications and skills courses. CONCLUSIONS: Online interviews were preferred over in-person interviews by most students. The lack of strong significant correlations between interview scores and grades suggests that use be judiciously applied in the overall admissions decision-making process.

Transitivity and degree assortativity explained: The bipartite structure of social networks.

Dynamical processes, such as the diffusion of knowledge, opinions, pathogens, "fake news," innovation, and others, are highly dependent on the structure of the social network in which they occur. However, questions on why most social networks present some particular structural features, namely, high levels of transitivity and degree assortativity, when compared to other types of networks remain open. First, we argue that every one-mode network can be regarded as a projection of a bipartite network, and we show that this is the case using two simple examples solved with the generating functions formalism. Second, using synthetic and empirical data, we reveal how the combination of the degree distribution of both sets of nodes of the bipartite network-together with the presence of cycles of lengths four and six-explain the observed values of transitivity and degree assortativity coefficients in the one-mode projected network. Bipartite networks with top node degrees that display a more right-skewed distribution than the bottom nodes result in highly transitive and degree assortative projections, especially if a large number of small cycles are present in the bipartite structure.

Bayesian estimation of pharmacokinetic parameters: an important component to include in the teaching of clinical pharmacokinetics and therapeutic drug monitoring.

Bayesian estimation of pharmacokinetic parameters (PKP), as discussed in this review, provides a powerful approach towards the individualization of dosing regimens. The method was first described by Lewis Sheiner and colleagues and it is well suited in clinical environs where few blood fluid measures of drugs are available in the clinic. This makes it a valuable tool in the effective implementation of therapeutic drug monitoring. The principle behind the method is Bayes theorem, which incorporates elements of variability in a priori-known population estimates and variability in the pharmacokinetic parameters, and known errors intrinsic to the assay method used to estimate the blood fluid drug concentrations. This manuscript reviews the Bayesian method. The literature was scanned using Pubmed to provide background into the Bayesian method. An Add-in for Excel program was used to show the ability of the method to estimate PKP using sparse blood fluid concentration vs time data. Using a computer program, the method was able to find reasonable estimates of individual pharmacokinetic parameters, assessed by comparing the estimated data to the true PKP. Education of students in clinical pharmacokinetics is incomplete without some mention and instruction of the Bayesian forecasting method. For a complete understanding, a computer program is needed to demonstrate its utility.

Entropy of Co-Enrolment Networks Reveal Disparities in High School STEM Participation.

The current study uses a network analysis approach to explore the STEM pathways that students take through their final year of high school in Aotearoa New Zealand. By accessing individual-level microdata from New Zealand's Integrated Data Infrastructure, we are able to create a co-enrolment network comprised of all STEM assessment standards taken by students in New Zealand between 2010 and 2016. We explore the structure of this co-enrolment network though use of community detection and a novel measure of entropy. We then investigate how network structure differs across sub-populations based on students' sex, ethnicity, and the socio-economic-status (SES) of the high school they attended. Results show the structure of the STEM co-enrolment network differs across these sub-populations, and also changes over time. We find that, while female students were more likely to have been enrolled in life science standards, they were less well represented in physics, calculus, and vocational (e.g., agriculture, practical technology) standards. Our results also show that the enrollment patterns of Asian students had lower entropy, an observation that may be explained by increased enrolments in key science and mathematics standards. Through further investigation of differences in entropy across ethnic group and high school SES, we find that ethnic group differences in entropy are moderated by high school SES, such that sub-populations at higher SES schools had lower entropy. We also discuss these findings in the context of the New Zealand education system and policy changes that occurred between 2010 and 2016.

Dronedarone: the effect of diet-induced obesity on its metabolism and experimental hyperlipidemia on its metabolism and tissue distribution in the rat.

Dronedarone biodistribution in hyperlipidemia and dronedarone metabolism in hyperlipidemia or obesity were assessed. Male Sprague-Dawley rats were given either normal standard chow with water or various high-fat or high-carbohydrate diets for 14 weeks. There was also a nonobese hyperlipidemic group given poloxamer 407 intraperitoneally. Liver and intestinal microsomes were prepared and the metabolic conversion of dronedarone to desbutyldronedarone was followed. A biodistribution study of dronedarone given orally was conducted in hyperlipidemic and control normolipidemic rats. The metabolism of dronedarone to desbutyldronedarone in control rats was consistent with substrate inhibition. However in the treatment groups, the formation of desbutyldronedarone did not follow substrate inhibition; hyperlipidemia and high-calorie diets created remarkable changes in dronedarone metabolic profiles and reduction in formation velocities. Tissue concentrations of dronedarone were much higher than in plasma. Furthermore, in hyperlipidemia, plasma and lung dronedarone concentrations were significantly higher compared to normolipidemia.

Dietary-Induced Obesity, Hepatic Cytochrome P450, and Lidocaine Metabolism: Comparative Effects of High-Fat Diets in Mice and Rats and Reversibility of Effects With Normalization of Diet.

The effects of a high-fat diet on mRNA and protein of cytochrome P450 (CYP) enzymes in rats and mice and its impact on lidocaine deethylation to its main active metabolite, monoethylglycinexylidide (MEGX), in rats were investigated. The effect of a change in diet from high-fat to standard diet was also evaluated. Plasma biochemistry, mRNA, protein expression for selected CYP, and the activity of lidocaine deethylation were determined. The high-fat diet curtailed the activity and the expression of the majority of CYPs (CYP1A2, CYP3A1, CYP2C11, CYP2C12, and CYP2D1), mRNA levels (Cyp1a2 and Cyp3a2), and MEGX maximal formation rate (Vmax). Mice showed complementary results in their protein expressions of cyp3a and 1a2. Switching the diet back to standard chow in rats for 4 weeks reverted the expression levels of mRNA and protein back to normal levels as well as the maximum formation rates of MEGX. Female and male rodents showed similar patterns in CYP expression and lidocaine metabolism in response to the diets, although MEGX formation was faster in male rats. In conclusion, diet-induced obesity caused general decreases in CYP isoforms not only in rats but also in mice. The effects were shown to be reversible in rats by normalizing the diet.