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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
#1
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) was 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...
June 22, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28636998/physiologically-based-pharmacokinetic-modeling-for-predicting-irinotecan-exposure-in-human-body
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28569994/physiologically-based-pharmacokinetic-modeling-for-predicting-the-effect-of-intrinsic-and-extrinsic-factors-on-darunavir-or-lopinavir-exposure-coadministered-with-ritonavir
#12
Christian Wagner, Ping Zhao, Vikram Arya, Charu Mullick, Kimberly Struble, Stanley Au
Management of comorbidities and medications is complex in HIV-1-infected patients. The overall objective of this project was to develop separate physiologically based pharmacokinetic (PBPK) substrate models for the protease inhibitors darunavir and lopinavir. These protease inhibitors are used in the treatment of HIV infection. Both darunavir and lopinavir are coadministered with another medication that inhibits cytochrome (CYP) 3A. The current project focused on PBPK modeling for darunavir and lopinavir coadministered with ritonavir...
June 1, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28568482/diffusion-limited-pbpk-model-for-predicting-pulmonary-pharmacokinetics-of-florfenicol-in-pig
#13
M R Qian, Q Y Wang, H Yang, G Z Sun, X B Ke, L L Huang, J D Gao, J J Yang, B Yang
For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been thought to be responsible for antimicrobial efficacy. In this study, a diffusion-limited physiologically based pharmacokinetic (PBPK) model was developed to predict the pulmonary pharmacokinetics of florfenicol (FF) in pigs. The model included separate compartments corresponding to blood, diffusion-limited lung, flow-limited muscle, liver, and kidney and an extra compartment representing the remaining carcass...
June 1, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28552429/prediction-of-renal-transporter-mediated-drug-drug-interactions-for-a-drug-which-is-an-oat-substrate-and-inhibitor-using-pbpk-modelling
#14
Kathryn Ball, Tanguy Jamier, Yannick Parmentier, Claire Denizot, Agnes Mallier, Marylore Chenel
A PBPK modelling approach was used to predict organic anion transporter (OAT) mediated drug-drug interactions involving S44121, a substrate and an inhibitor of OAT1 and OAT3. Model predictions were then compared to the results of a clinical DDI study which was carried out to investigate the interaction of S44121 with probenecid, tenofovir and ciprofloxacin. PBPK models were developed and qualified using existing clinical data, and inhibition constants were determined in vitro. The model predictions for S44121 as an OAT inhibitor were similar to the results obtained from the clinical DDI study, with no interaction observed for tenofovir or ciprofloxacin in the presence of S44121...
May 25, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28546104/development-of-a-paediatric-physiologically-based-pharmacokinetic-model-to-assess-the-impact-of-drug-drug-interactions-in-tuberculosis-co-infected-malaria-subjects-a-case-study-with-artemether-lumefantrine-and-the-cyp3a4-inducer-rifampicin
#15
Olusola Olafuyi, Michael Coleman, Raj K S Badhan
The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure...
May 22, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28541457/bumped-kinase-inhibitor-gastrointestinal-exposure-is-necessary-to-treat-cryptosporidium-infection
#16
Samuel L M Arnold, Ryan Choi, Matthew A Hulverson, Deborah A Schaefer, Sumiti Vinayak, Rama S R Vidadala, Molly C McCloskey, Grant R Whitman, Wenlin Huang, Lynn K Barrett, Kayode K Ojo, Erkang Fan, Dustin J Maly, Michael W Riggs, Boris Striepen, Wesley C Van Voorhis
There is a substantial need for novel therapeutics to combat the widespread impact caused by Crytosporidium infection. However, there is a lack of knowledge on which drug pharmacokinetic characteristics are key to generate an in vivo response specifically if systemic drug exposure is crucial for in vivo efficacy. To identify which pharmacokinetic properties are correlated with in vivo efficacy, we generated physiologically based pharmacokinetic (PBPK) models to simulate systemic and gastrointestinal (GI) drug concentrations for a series of bumped kinase inhibitors (BKI) that have nearly identical in vitro potency against Cryptosporidium but display divergent pharmacokinetic properties...
May 24, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28536774/physiologically-based-pharmacokinetic-modelling-and-prediction-of-metformin-pharmacokinetics-in-renal-hepatic-impaired-young-adults-and-elderly-populations
#17
Su-Jin Rhee, Hyewon Chung, SoJeong Yi, Kyung-Sang Yu, Jae-Yong Chung
BACKGROUND AND OBJECTIVES: Physiologically based pharmacokinetic (PBPK) modelling and simulation enable researchers to overcome practical limitations for clinical trials on special populations. This study was conducted to investigate how the PBPK model describes the pharmacokinetics of metformin in young adult and elderly populations and to predict the pharmacokinetics of metformin in patients with renal or hepatic impairment in both populations. METHODS: A first-order absorption/PBPK model for metformin was built in the Simcyp simulator version 14 release 1...
May 23, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28526963/incorporation-of-the-time-varying-postprandial-increase-in-splanchnic-blood-flow-into-a-pbpk-model-to-predict-the-effect-of-food-on-the-pharmacokinetics-of-orally-administered-high-extraction-drugs
#18
Rachel H Rose, David B Turner, Sibylle Neuhoff, Masoud Jamei
Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q Splanch) was developed to describe the observed data for healthy individuals...
May 19, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28522410/a-global-human-health-risk-assessment-for-octamethylcyclotetrasiloxane-d4
#19
Robinan Gentry, Allison Franzen, Cynthia Van Landingham, Tracy Greene, Kathy Plotzke
Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight volatile cyclic siloxane, primarily used as an intermediate in the production of some widely-used industrial and consumer silicone based polymers and may be present as a component in a variety of consumer products. A global "harmonized" risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA's Integrated Risk Information System (IRIS), Health Canada's Chemical Management Program (CMP) and various independent scientific committees of the European Commission (e...
May 15, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28514845/in-vivo-mercury-demethylation-in-a-marine-fish-acanthopagrus-schlegeli
#20
Xun Wang, Fengchang Wu, Wen-Xiong Wang
Mercury (Hg) in fish has attracted public attention for decades, and methylmercury (MeHg) is the predominant form in fish. However, the in vivo MeHg demethylation and its influence on Hg level in fish have not been well-addressed. The present study investigated the in vivo demethylation process in a marine fish (black seabream, Acanthopagrus schlegeli) under dietary MeHg exposure and depuration and quantified the biotransformation and interorgan transportation of MeHg by developing a physiologically based pharmacokinetic (PBPK) model...
June 6, 2017: Environmental Science & Technology
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