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Keyvin Darney, Laurent Bodin, Michèle Bouchard, Jonathan Côté, Jean-Luc Volatier, Virginie Desvignes
The French Nutrition and Health Survey (ENNS) reported higher biomarker levels of exposure to pyrethroids than those observed in North American and German biomonitoring studies. The authors therefore investigated aggregate exposure to permethrin as an initial case study because this compound is one of the most widely-used pyrethroid insecticides. We assessed several contamination sources-such as indoor and outdoor air, settled dust and diet-and several pathways, including oral, inhalation and dermal routes...
May 9, 2018: Toxicology and Applied Pharmacology
Ulrika Carlander, Tshepo Paulsen Moto, Anteneh Assefa Desalegn, Robert A Yokel, Gunnar Johanson
Background: Cerium dioxide nanoparticles (nanoceria) are increasingly being used in a variety of products as catalysts, coatings, and polishing agents. Furthermore, their antioxidant properties make nanoceria potential candidates for biomedical applications. To predict and avoid toxicity, information about their biokinetics is essential. A useful tool to explore such associations between exposure and internal target dose is physiologically based pharmacokinetic (PBPK) modeling. The aim of this study was to test the appropriateness of our previously published PBPK model developed for intravenous (IV) administration when applied to various sizes of nanoceria and to exposure routes relevant for humans...
2018: International Journal of Nanomedicine
Peter Kletting, Anne Thieme, Nina Eberhardt, Andreas Rinscheid, Calogero D'Alessandria, Jakob Allmann, Hans-Jürgen Wester, Robert Tauber, Ambros J Beer, Gerhard Glatting, Matthias Eiber
The aim of this work was to develop a theranostic method that allows predicting PSMA-positive tumor volume after radioligand therapy (RLT) based on a pre-therapeutic PET/CT measurement and physiologically based pharmacokinetic/dynamic (PBPK/PD) modeling at the example of RLT using 177 Lu-labeled PSMA for imaging and therapy (PSMA I&T). Methods: A recently developed PBPK model for 177 Lu PSMA I&T RLT was extended to account for tumor (exponential) growth and reduction due to irradiation (linear quadratic model)...
May 10, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Shinji Yamazaki, Cho-Ming Loi, Emi Kimoto, Chester Costales, Manthena V Varma
Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supra-proportional at the lower doses (50 to 200 mg) and approximately dose-proportional at the higher doses (200 to 600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability...
May 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jan-Frederik Schlender, Donato Teutonico, Katrin Coboeken, Katrin Schnizler, Thomas Eissing, Stefan Willmann, Ulrich Jaehde, Heino Stass
BACKGROUND: Physiologically-based pharmacokinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics by continuous knowledge integration. OBJECTIVE: The objective of this study was to build a ciprofloxacin PBPK model for intravenous and oral dosing based on a comprehensive literature review, and evaluate the predictive performance towards pediatric and geriatric patients. METHODS: The aim of this report was to establish confidence in simulations of the ciprofloxacin PBPK model along the development process to facilitate reliable predictions outside of the tested adult age range towards the extremes of ages...
May 8, 2018: Clinical Pharmacokinetics
Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-Jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon, Dong-Seok Yim
It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure...
May 2018: Korean Journal of Physiology & Pharmacology
Katherine Kay, Dhaval K Shah, Lisa Rohan, Robert Bies
AIMS: A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring [1] or film [2]. METHODS: A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB...
May 1, 2018: British Journal of Clinical Pharmacology
Yoshiaki Yao, Kota Toshimoto, Soo-Jin Kim, Takashi Yoshikado, Yuichi Sugiyama
Cerivastatin (CER) was withdrawn from the world market because of lethal rhabdomyolysis. Coadministrations of CER and cyclosporine A (CsA) or gemfibrozil (GEM) have been reported to increase the CER blood concentration. CsA is an inhibitor of OATP1B1 and CYP3A4, and GEM and its glucuronide (GEM-glu) inhibit OATP1B1 and CYP2C8. The purpose of this study was to describe the transporter-/enzymemediated drug-drug interactions (DDIs) of CER with CsA or GEM based on unified physiologically based pharmacokinetic (PBPK) models and to investigate whether the DDIs can be quantitatively analyzed by a bottom-up approach...
April 30, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Tomonori Miura, Hiroshi Suemizu, Masatomo Goto, Norifumi Sakai, Hiroshi Iwata, Makiko Shimizu, Hiroshi Yamazaki
1. Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-14 C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined. 2. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice...
April 30, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Anum Munir, Shumaila Azam, Sahar Fazal, A I Bhatti
The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption...
April 25, 2018: Journal of Theoretical Biology
Bhagwat Prasad, Deepak Kumar Bhatt, Katherine Johnson, Revathi Chapa, Xiaoyan Chu, Laurent Salphati, Guangqing Xiao, Caroline Lee, Cornelis Eca Hop, Anita Mathias, Yurong Lai, Mingxiang Liao, W Griffith Humphreys, Sean C Kumer, Jashvant D Unadkat
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various Phase I and Phase II drug metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n=27) or hepatitis C (HCV, n=30) cirrhotic vs. non-cirrhotic (control) livers (n=25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic vs. control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8 vs. 51.1 ± 20.7 mg/g liver, respectively)...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Todd J Zurlinden, Brad Reisfeld
BACKGROUND: Organophosphorus (OP) compounds are the most widely used group of insecticides in the world. Risk assessments for these chemicals have focused primarily on 10% inhibition of acetylcholinesterase in the brain as the critical metric of effect. Aside from cholinergic effects resulting from acute exposure, many studies suggest a linkage between cognitive deficits and long-term OP exposure. OBJECTIVE: In this proof-of-concept study, we focused on one of the most widely used OP insecticides in the world, chlorpyrifos (CPF), and utilized an existing physiologically based pharmacokinetic (PBPK) model and a novel pharmacodynamic (PD) dose-response model to develop a point of departure benchmark dose estimate for cognitive deficits following long-term, low-dose exposure to this chemical in rodents...
April 20, 2018: Environmental Health Perspectives
Xiaowei Zang, Leonid Kagan
The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol-Taxol® ) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration-time data following single intravenous bolus administration of Taxol® to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments...
April 18, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Salim Bouchene, Sandrine Marchand, William Couet, Lena E Friberg, Patrice Gobin, Isabelle Lamarche, Nicolas Grégoire, Sven Björkman, Mats O Karlsson
Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, Kp . Colistin and its prodrug, colistin methanesulfonate (CMS) Kp priors were measured experimentally from rat tissue homogenates or predicted in silico...
April 17, 2018: Basic & Clinical Pharmacology & Toxicology
Miguel Ángel Cabrera-Pérez, Hai Pham-The
The oral route is the most convenient way of administrating drugs. Therefore, accurate determination of oral bioavailability is paramount during drug discovery and development. Quantitative structure-property relationship (QSPR), rule-of-thumb (RoT) and physiologically based-pharmacokinetic (PBPK) approaches are promising alternatives to the early oral bioavailability prediction. Areas covered: The authors give insight into the factors affecting bioavailability, the fundamental theoretical framework and the practical aspects of computational methods for predicting this property...
April 17, 2018: Expert Opinion on Drug Discovery
Yi-Hsien Cheng, Jim E Riviere, Nancy A Monteiro-Riviere, Zhoumeng Lin
This study aimed to conduct an integrated and probabilistic risk assessment of gold nanoparticles (AuNPs) based on recently published in vitro and in vivo toxicity studies coupled to a physiologically based pharmacokinetic (PBPK) model. Dose-response relationships were characterized based on cell viability assays in various human cell types. A previously well-validated human PBPK model for AuNPs was applied to quantify internal concentrations in liver, kidney, skin, and venous plasma. By applying a Bayesian-based probabilistic risk assessment approach incorporating Monte Carlo simulation, probable human cell death fractions were characterized...
April 14, 2018: Nanotoxicology
Sarah R Delaney, Paul R V Malik, Cristiana Stefan, Andrea N Edginton, David A Colantonio, Shinya Ito
BACKGROUND: Escitalopram is used for post-partum depression; however, there are limited pharmacokinetic data of escitalopram in milk and plasma of infants breastfed by women taking the drug. OBJECTIVE: The objective of this study was to apply physiologically-based pharmacokinetic (PBPK) modelling to predict infant drug exposure (plasma area under the curve from time zero to infinity [AUC∞ ]) based on drug monitoring data of escitalopram in breast milk. METHODS: Using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we quantified escitalopram concentrations in milk samples of 18 breastfeeding women with escitalopram therapy at steady state, collected at three to five time points...
April 12, 2018: Clinical Pharmacokinetics
Cai-Fu Xue, Zhe Zhang, Yan Jin, Bin Zhu, Jun-Fen Xing, Guo Ma, Xiao-Qiang Xiang, Wei-Min Cai
Liver metabolism is commonly considered the major determinant in drug discovery and development. Many in vitro drug metabolic studies have been developed and applied to understand biotransformation. However, these methods have disadvantages, resulting in inconsistencies between in vivo and in vitro experiments. A major factor is that they are static systems that do not consider the transport process in the liver. Here we developed an in vitro dynamic metabolic system (Bio-PK metabolic system) to mimic the human pharmacokinetics of tolbutamide...
April 12, 2018: Acta Pharmacologica Sinica
Ling Song, Yi Zhang, Ji Jiang, Shuang Ren, Li Chen, Dongyang Liu, Xijing Chen, Pei Hu
AIM: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. METHODS: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms...
April 6, 2018: Clinical Pharmacokinetics
Keigo Nakayama, Soichiro Ito, Masahiro Suzuki, Hiroaki Takubo, Hiroshi Yamazaki, Yukihiro Nomura
1. In this study, total body clearance (CLt ), volume of distribution at steady state (Vss ) and plasma concentration-time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. 2. On the basis of assumption that unbound intrinsic clearance (CLUint ) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp ) in chimeric mice estimated from a difference between the observed and predicted Vss ...
April 5, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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