Cytochromes P450 (CYPs) are a superfamily of enzymes that metabolize the majority of xenobiotics in humans. This review presents a structure-based outline of CYP-catalyzed biotransformations of selected substrates, representing diverse structural classes of chemicals, ranging from drugs to toxicants. Data are presented in a tabular format for easy reference, with visual representations of all substrates and sites-of-attack. The major metabolites, isozymes responsible, chemical classification, and other information related to the biotransformation are provided. Pharmacophores proposed for the major CYP isozymes are discussed. This visual combination of substrates and biotransformation sites can serve as a useful reference for researchers.
BackgroundOne problem of interpreting population-based biomonitoring data is the reconstruction of corresponding external exposure in cases where no such data are available.ObjectivesWe demonstrate the use of a computational framework that integrates physiologically based pharmacokinetic (PBPK) modeling, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of environmental chloroform source concentrations consistent with human biomonitoring data. The biomonitoring data consist of chloroform blood concentrations measured as part of the Third National Health and Nutrition Examination Survey (NHANES III), and for which no corresponding exposure data were collected.MethodsWe used a combined PBPK and shower exposure model to consider several routes and sources of exposure: ingestion of tap water, inhalation of ambient household air, and inhalation and dermal absorption while showering. We determined posterior distributions for chloroform concentration in tap water and ambient household air using U.S. Environmental Protection Agency Total Exposure Assessment Methodology (TEAM) data as prior distributions for the Bayesian analysis.ResultsPosterior distributions for exposure indicate that 95% of the population represented by the NHANES III data had likely chloroform exposures ≤ 67 μg/L in tap water and ≤ 0.02 μg/L in ambient household air.ConclusionsOur results demonstrate the application of computer simulation to aid in the interpretation of human biomonitoring data in the context of the exposure–health evaluation–risk assessment continuum. These results should be considered as a demonstration of the method and can be improved with the addition of more detailed data.
We consider the flow of a viscous liquid film on the surface of a cylinder that is heated or cooled. Lubrication theory is used to study a thin film under the influence of gravity, capillary, thermocapillary, and intermolecular forces. We derive evolution equations for the interface shapes as a function of the azimuthal angle about the cylinder that govern the behaviour of the film subject to the above coupled forces. We use both analytical and numerical techniques to elucidate the dynamics and steady states of the thin layer over a wide range of thermal conditions and material properties. Finally, we extend our derivation to the case of three-dimensional dynamics and explore the stability of the film to small axial disturbances.
Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31–2.21), (ii) 5.65; (A-S+, 3.38–9.42), (iii) 8.70 (A+S+, 5.8–13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26–1.77) and the multiplicative index = 0.91 (95% CI = 0.63–1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00–1.28) and 0.51 (95% CI = 0.31–0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits.
A fixed volume of liquid is placed on a horizontal disk spinning at a constant angular speed. The liquid forms a film that thins continuously due to centrifugal drainage and evaporation or thins to a finite thickness when surface absorption counterbalances drainage. A nonlinear evolution equation describing the shape of the film interface as a function of space and time is derived, and its stability is examined using linear theory. When there is either no mass transfer or there is evaporation from the film surface, infinitesimal disturbances decay for small wave numbers and are transiently stable for larger wave numbers. When absorption is present at the free surface, the film exhibits three different domains of stability: disturbances of small wave numbers decay, disturbances of intermediate wave numbers grow transiently, and those of larger wave numbers grow exponentially.
One problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to Mycobacterium tuberculosis infection, and pharmacokinetic models for other anti-TB drugs.T uberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease which continues to be a major cause of death in large parts of the world (1). While the current first-line therapy for drug-susceptible TB (composed of rifampin, isoniazid, pyrazinamide, and ethambutol) has been in clinical use for nearly 30 years, the emergence and spread of drug-resistant M. tuberculosis strains have motivated the search for new, more-effective combination regimens (2). Our interest here is the development of mathematical tools to supplement the animal studies necessary for the identification and testing of such new anti-TB drug regimens.The mouse is the primary animal species used for preclinical anti-TB drug development (3). Despite the differences between mice and humans, the activities of many anti-TB drugs against disease caused by M. tuberculosis are similar in both species (4, 5). Mice also provide for a range of TB susceptibility and pathology through a variety of outbred and inbred strains; a notable example is C3HeB/FeJ mice (6), which form necrotic pulmonary lesions similar to those observed in TB patients (7). The recent Critical Path to TB Drug Regimens (CPTR) Initiative (8) includes an added emphasis on the mouse for identification of new optimized three-drug regimens as a key step in advancing novel drug combinations into ...
Traditionally, the solution to reduce parameter dimensionality in a physiologically-based pharmacokinetic (PBPK) model is through expert judgment. However, this approach may lead to bias in parameter estimates and model predictions if important parameters are fixed at uncertain or inappropriate values. The purpose of this study was to explore the application of global sensitivity analysis (GSA) to ascertain which parameters in the PBPK model are non-influential, and therefore can be assigned fixed values in Bayesian parameter estimation with minimal bias. We compared the elementary effect-based Morris method and three variance-based Sobol indices in their ability to distinguish “influential” parameters to be estimated and “non-influential” parameters to be fixed. We illustrated this approach using a published human PBPK model for acetaminophen (APAP) and its two primary metabolites APAP-glucuronide and APAP-sulfate. We first applied GSA to the original published model, comparing Bayesian model calibration results using all the 21 originally calibrated model parameters (OMP, determined by “expert judgment”-based approach) vs. the subset of original influential parameters (OIP, determined by GSA from the OMP). We then applied GSA to all the PBPK parameters, including those fixed in the published model, comparing the model calibration results using this full set of 58 model parameters (FMP) vs. the full set influential parameters (FIP, determined by GSA from FMP). We also examined the impact of different cut-off points to distinguish the influential and non-influential parameters. We found that Sobol indices calculated by eFAST provided the best combination of reliability (consistency with other variance-based methods) and efficiency (lowest computational cost to achieve convergence) in identifying influential parameters. We identified several originally calibrated parameters that were not influential, and could be fixed to improve computational efficiency without discernable changes in prediction accuracy or precision. We further found six previously fixed parameters that were actually influential to the model predictions. Adding these additional influential parameters improved the model performance beyond that of the original publication while maintaining similar computational efficiency. We conclude that GSA provides an objective, transparent, and reproducible approach to improve the performance and computational efficiency of PBPK models.
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