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https://www.readbyqxmd.com/read/28715785/prenatal-exposure-estimation-of-bpa-and-dehp-using-integrated-external-and-internal-dosimetry-a-case-study
#1
M A Martínez, J Rovira, R Prasad Sharma, M Nadal, M Schuhmacher, V Kumar
Prenatal exposure to Endocrine disruptors (EDs), such as Bisphenol A (BPA) and di (2-ethylhexyl) phthalate (DEHP), has been associated with obesity and diabetes diseases in childhood, as well as reproductive, behavioral and neurodevelopment problems. The aim of this study was to estimate the prenatal exposure to BPA and DEHP through food consumption for pregnant women living in Tarragona County (Spain). Probabilistic calculations of prenatal exposure were estimated by integrated external and internal dosimetry modelling, physiologically based pharmacokinetic (PBPK) model, using a Monte-Carlo simulation...
July 14, 2017: Environmental Research
https://www.readbyqxmd.com/read/28710684/utility-of-physiologically-based-pharmacokinetic-absorption-modeling-to-predict-the-impact-of-salt-to-base-conversion-on-prasugrel-hcl-product-bioequivalence-in-the-presence-of-proton-pump-inhibitors
#2
Jianghong Fan, Xinyuan Zhang, Liang Zhao
Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility...
July 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28688108/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-buprenorphine-pharmacokinetics-following-intravenous-sublingual-administration
#3
Hari V Kalluri, Hongfei Zhang, Steve N Caritis, Raman Venkataramanan
INTRODUCTION: Opioid dependence is associated with high morbidity and mortality. Buprenorphine(BUP) is approved by the FDA to treat opioid dependence. There is a lack of clear consensus on appropriate dosing of BUP due to inter-patient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of this study is to build and validate robust physiologically-based-pharmacokinetic(PBPK) models for intravenous(IV) and Sublingual(SL) BUP as a first-step to optimize BUP pharmacotherapy...
July 8, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28684146/physiologically-based-pharmacokinetic-modeling-of-human-exposure-to-perfluorooctanoic-acid-suggests-historical-non-drinking-water-exposures-are-important-for-predicting-current-serum-concentrations
#4
Rachel Rogers Worley, Xiaoxia Yang, Jeffrey Fisher
Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations...
July 3, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28681680/evolution-of-chemical-specific-adjustment-factors-csaf-based-on-recent-international-experience-increasing-utility-and-facilitating-regulatory-acceptance
#5
Virunya S Bhat, M E Bette Meek, Mathieu Valcke, Caroline English, Alan Boobis, Richard Brown
The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U...
July 6, 2017: Critical Reviews in Toxicology
https://www.readbyqxmd.com/read/28676206/manganese-testing-under-a-clean-air-act-test-rule-and-the-application-of-resultant-data-in-risk-assessments
#6
Darcie Smith, George M Woodall, Annie M Jarabek, William K Boyes
In the 1990's, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use...
July 1, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28672700/using-exposure-prediction-tools-to-link-exposure-and-dosimetry-for-risk-based-decisions-a-case-study-with-phthalates
#7
Marjory Moreau, Jeremy Leonard, Katherine A Phillips, Jerry Campbell, Salil N Pendse, Chantel Nicolas, Martin Phillips, Miyoung Yoon, Yu-Mei Tan, Sherrie Smith, Harish Pudukodu, Kristin Isaacs, Harvey Clewell
A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors...
June 24, 2017: Chemosphere
https://www.readbyqxmd.com/read/28669739/an-evidence-based-recommendation-to-increase-the-dosing-frequency-of-buprenorphine-during-pregnancy
#8
Steve N Caritis, Jaime R Bastian, Hongfei Zhang, Hari Kalluri, Dennis English, Michael England, Stephanie Bobby, Raman Venkataramanan
BACKGROUND: Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared to the non-pregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than non-pregnant individuals in order to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered but the frequency of dosing is not clearly addressed...
June 29, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/28663311/the-use-of-physiology-based-pk-and-pd-modeling-in-the-discovery-of-the-dual-orexin-receptor-antagonist-act-541468
#9
Alexander Treiber, Ruben de Kanter, Catherine Roch, John Gatfield, Christoph Boss, Markus von Raumer, Benno Schindelholz, Clemens Muehlan, Joop van Gerven, Francois Jenck
The identification of new sleep drugs poses particular challenges in drug discovery due to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging in case inter-species differences are prominent...
June 29, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28640606/pharmacokinetics-of-mequindox-and-its-marker-residue-1-4-bisdesoxymequindox-in-swine-following-multiple-oral-gavage-and-intramuscular-administration-an-experimental-study-coupled-with-population-physiologically-based-pharmacokinetic-modeling
#10
Dongping Zeng, Zhoumeng Lin, Binghu Fang, Miao Li, Ronette Gehring, Jim E Riviere, Zhenling Zeng
Mequindox (MEQ) is a quinoxaline-N,N-dioxide antibiotic used in food-producing animals. MEQ residue in animal-derived foods is a food safety concern. The tissue distribution of MEQ and its marker residue 1,4-bisdesoxymequindox (M1) were determined in swine following oral gavage or intramuscular injection twice daily for 3 days. The experimental data were used to construct a flow-limited physiologically based pharmacokinetic (PBPK) model. The model predictions correlated with available data well. Monte Carlo analysis showed that the times needed for M1 concentrations to fall below limit of detection (5 μg/kg) in liver for the 99th percentile of the population were 27 and 34 days after oral gavage and intramuscular administration twice daily for 3 days, respectively...
July 5, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28636998/physiologically-based-pharmacokinetic-modeling-for-predicting-irinotecan-exposure-in-human-body
#11
Yingfang Fan, Najia Mansoor, Tasneem Ahmad, Rafeeq Alam Khan, Martin Czejka, Syed Sharib, Dong-Hua Yang, Mansoor Ahmed
Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28627373/development-and-application-of-a-population-physiologically-based-pharmacokinetic-model-for-penicillin-g-in-swine-and-cattle-for-food-safety-assessment
#12
Miao Li, Ronette Gehring, Jim E Riviere, Zhoumeng Lin
Penicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle...
June 13, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28615288/correlation-between-apparent-substrate-affinity-and-oct2-transporter-turnover
#13
Alyscia Cory Severance, Philip J Sandoval, Stephen H Wright
Organic cation transporter 2 (OCT2) mediates the first step in the renal secretion of many cationic drugs: basolateral uptake from blood into proximal tubule cells. The impact of this process on the pharmacokinetics of drug clearance as estimated using a physiologically-based pharmacokinetic (PBPK) approach relies on an accurate understanding of the kinetics of transport because the ratio of the maximal rate of transport to the Michaelis constant (i.e., Jmax/Kt) provides an estimate of the intrinsic clearance (Clint) used in in vitro-in vivo extrapolation of experimentally determined transport data...
June 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28613103/quantification-of-igg-monoclonal-antibody-clearance-in-tissues
#14
Miro J Eigenmann, Ludivine Fronton, Hans Peter Grimm, Michael B Otteneder, Ben-Fillippo Krippendorff
Monoclonal antibodies are an important therapeutic entity, and knowledge of antibody pharmacokinetics has steadily increased over the years. Despite this effort, little is known about the extent of IgG antibody degradation in different tissues of the body. While studies have been published identifying sites of degradation with the use of residualizing and non-residualizing radiolabels, quantitative tissue clearances have not yet been derived. Here, we show that in physiologically-based pharmacokinetic (PBPK) models we can combine mouse data of Indium-111 and Iodine-125 labeled antibodies with prior physiological knowledge to determine tissue-specific intrinsic clearances...
June 14, 2017: MAbs
https://www.readbyqxmd.com/read/28608515/efavirenz-clearances-in-vitro-and-in-vivo-in-six-cynomolgus-monkeys-associated-with-polymorphic-cytochrome-p450-2c9-and-simulated-by-individual-physiologically-based-pharmacokinetic-models
#15
Masahiro Utoh, Tomonori Miura, Takashi Kusama, Shotaro Uehara, Makiko Shimizu, Yasuhiro Uno, Hiroshi Yamazaki
Cynomolgus monkey cytochrome P450 2C9 (formerly known as P450 2C43) variation was reportedly associated with metabolic clearance of the antiretroviral drug efavirenz in vivo (of three wild-type, one heterozygote, and two homozygote animals), being unlikely in the case of human P450 2B6-dependent efavirenz clearance. In this study, the liver microsomal elimination rates of efavirenz for the same individual animals previously treated with intravenous/oral administrations of efavirenz showed significant reductions associated with the P450 2C9 p...
June 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28603626/physiologically-based-pharmacokinetic-modeling-of-tea-catechin-mixture-in-rats-and-humans
#16
Francis C P Law, Meicun Yao, Hui-Chang Bi, Stephen Lam
Although green tea (Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28589509/strategies-of-drug-transporter-quantitation-by-lc-ms-importance-of-peptide-selection-and-digestion-efficiency
#17
Buyun Chen, Liling Liu, Hoangdung Ho, Yuan Chen, Ze Yang, Xiaorong Liang, Jian Payandeh, Brian Dean, Cornelis E C A Hop, Yuzhong Deng
Huge variation of drug transporter abundance was seen in the literature, making PBPK prediction difficult when transporters play a major role. Among multiple factors such as membrane fraction, digestion, and peptide selection that contributed to such variation, peptide selection is the least discussed. Herein, a strategy was established by using a small amount of purified protein standard to select a peptide with near 100% digestion efficiency for quantitation of a transporter protein MDR1. The impact of native membrane protein's tertiary structure on the digestion efficiency of surrogate peptides of MDR1 was investigated...
June 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28588050/development-of-a-novel-maternal-fetal-physiologically-based-pharmacokinetic-model-i-insights-into-factors-that-determine-fetal-drug-exposure-through-simulations-and-sensitivity-analyses
#18
Zufei Zhang, Marjorie Z Imperial, Gabriela I Patilea-Vrana, Janak Wedagedera, Lu Gaohua, Jashvant D Unadkat
Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age-dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: (1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug dosing regimens administered to the mother; (2) predict the impact of gestational age on fetal drug exposure; and (3) demonstrate that a single umbilical venous: maternal plasma (UV:MP) ratio (even after multiple oral dose administration to steady-state) does not necessarily reflect fetal drug exposure...
June 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28585774/a-physiologically-based-pharmacokinetic-model-of-vitamin-d
#19
Megan E Sawyer, Hien T Tran, Marina V Evans
Despite the plethora of studies discussing the benefits of vitamin D on physiological functioning, few mathematical models of vitamin D predict the response of the body on low-concentration supplementation of vitamin D under sunlight-restricted conditions. This study developed a physiologically based pharmacokinetic (PBPK) model utilizing published human data on the metabolic cascade of orally derived, low-concentration (placebo, 5 μg and 10 μg) supplementation of vitamin D over the course of 28 days in the absence of sunlight...
June 6, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28571120/development-of-physiologically-based-organ-models-to-evaluate-the-pharmacokinetics-of-drugs-in-the-testes-and-the-thyroid-gland
#20
Sabine Pilari, Thomas Gaub, Michael Block, Linus Görlitz
We extended a generic whole-body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems, i.e., the testes and the thyroid gland. An extensive literature search was performed, firstly, to determine the most generic organ model structures for testes and thyroid across species and, secondly, to identify the corresponding anatomical and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK-Sim® and MoBi®...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
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