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https://www.readbyqxmd.com/read/29330218/a-study-on-pharmacokinetics-of-bosentan-with-systems-modeling-part-1-translating-systemic-plasma-concentration-to-liver-exposure-in-healthy-subjects
#1
Rui Li, Mark Niosi, Nathaniel Johnson, David A Tess, Emi Kimoto, Jian Lin, Xin Yang, Keith A Riccardi, Sangwoo Ryu, Ayman F El-Kattan, Tristan S Maurer, Larry M Tremaine, Li Di
Understanding liver exposure of hepatic transporter substrates in clinical studies is often critical as it typically governs pharmacodynamics, drug-drug interactions, and toxicity for certain drugs. However, this is a challenging task since there is currently no easy method to directly measure drug concentration in the human liver. Using bosentan as an example, a new approach has been demonstrated to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically-based pharmacokinetic modeling...
January 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29326367/organic-anion-transporter-2-mediates-hepatic-uptake-of-tolbutamide-a-cytochrome-p450-2c9-probe-drug
#2
Yi-An Bi, Sumathy Mathialagan, Laurie Tylaska, Myra Fu, Julie Keefer, Anna Vildhede, Chester Costales, A David Rodrigues, Manthena Varma
Tolbutamide is primarily metabolized by cytochrome P450 (CYP)2C9, and thus, frequently applied as a clinical probe substrate for CYP2C9 activity. However, there is a marked discrepancy in the in vitro-in vivo extrapolation of its metabolic clearance implying potential for additional clearance mechanisms. The goal of this study was to evaluate the role of hepatic uptake transport in the pharmacokinetics of tolbutamide and identify the molecular mechanism thereof. Transport studies using singly-transfected cells expressing six major hepatic uptake transporters showed that tolbutamide is a substrate to organic anion transporter (OAT)2 alone -- with transporter affinity (Km) of 19...
January 11, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29321333/microrna-130a-regulates-both-hcv-and-hbv-replication-through-a-central-metabolic-pathway
#3
Xiaoqiong Duan, Shilin Li, Jacinta A Holmes, Zeng Tu, Yujia Li, Dachuan Cai, Xiao Liu, Wenting Li, Chunhui Yang, Baihai Jiao, Esperance A Schaefer, Dahlene N Fusco, Shadi Salloum, Limin Chen, Wenyu Lin, Raymond T Chung
BACKGROUND: HCV infection has been shown to regulate miR-130a in patient biopsies and in cultured cells. We sought to identify miR-130a target genes and to explore the mechanisms by which miR-130a regulates HCV and HBV replication.METHODS: We used bioinformatics software including miRanda, TargetScan, PITA and RNAhybrid to predict potential miR-130a target genes. miR-130a and its target genes were overexpressed, or knocked down by siRNA or by CRISPR/Cas9 gRNA, respectively. Selected gene mRNAs and their proteins, together with HCV replication in OR6 cells, JFH1 HCV-infected Huh7...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29315257/post-modified-polypeptides-with-ucst-type-behavior-for-control-of-cell-attachment-in-physiological-conditions
#4
Xuan Xue, Lalitha Thiagarajan, James E Dixon, Brian R Saunders, Kevin M Shakesheff, Cameron Alexander
Upper Critical Solution Temperature (UCST)-type thermally responsive polypeptides (TRPs) with phase transition temperatures around 37 °C in phosphate-buffered saline (PBS) buffer (pH 7.4, 100 mM) were prepared from poly(l-ornithine) hydrobromide and coated on non-tissue culture-treated plastic plates (nTCP). Cell adhesion was observed at temperatures above the phase transition temperature of the coating polymer (39 °C), while cell release was triggered when the culture temperature was switched to 37 °C. Approximately 65% of the attached cells were released from the surface within 6 h after changing the temperature, and more than 96% of the released cells were viable...
January 9, 2018: Materials
https://www.readbyqxmd.com/read/29309877/development-of-a-mechanistic-biokinetic-model-for-hepatic-bile-acid-handling-to-predict-possible-cholestatic-effects-of-drugs
#5
Sylvia Notenboom, Karl M Weigand, Johannes H Proost, Marola M van Lipzig, Evita van de Steeg, Petra H H van den Broek, Rick Greupink, Frans G M Russel, Geny M M Groothuis
Drug-induced liver injury (DILI) is a common reason for drug withdrawal from the market. An important cause of DILI is drug-induced cholestasis. One of the major players involved in drug-induced cholestasis is the bile salt efflux pump (BSEP; ABCB11). Inhibition of BSEP by drugs potentially leads to cholestasis due to increased (toxic) intrahepatic concentrations of bile acids with subsequent cell injury. In order to investigate the possibilities for in silico prediction of cholestatic effects of drugs, we developed a mechanistic biokinetic model for human liver bile acid handling populated with human in vitro data...
January 5, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29309795/lipase-inhibitor-orlistat-prevents-hepatitis-b-virus-infection-by-targeting-an-early-step-in-the-virus-life-cycle
#6
Knud Esser, Julie Lucifora, Jochen Wettengel, Katrin Singethan, Almut Glinzer, Alma Zernecke, Ulrike Protzer
Hepatitis B Virus (HBV) is a strictly hepatotropic pathogen which is very efficiently targeted to the liver and into its host cell, the hepatocyte. The sodium taurocholate co-transporting polypeptide (NTCP) has been identified as a key virus entry receptor, but the early steps in the virus life cycle are still only barely understood. Here, we investigated the effect of lipase inhibition and lipoprotein uptake on HBV infection using differentiated HepaRG cells and primary human hepatocytes. We found that an excess of triglyceride rich lipoprotein particles in vitro diminished HBV infection and a reduced hepatic virus uptake in vivo if apolipoprotein E is lacking indicating virus transport along with lipoproteins to target hepatocytes...
January 5, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29300980/distinct-relapse-rates-and-risk-predictors-after-discontinuing-tenofovir-and-entecavir-therapy
#7
Tung-Hung Su, Hung-Chih Yang, Tai-Chung Tseng, Jyh-Ming Liou, Chen-Hua Liu, Chi-Ling Chen, Pei-Jer Chen, Ding-Shinn Chen, Chun-Jen Liu, Jia-Horng Kao
Background: We investigated the patterns; predictors for virological relapse (VR), clinical relapse (CR), sustained clinical response (SCR); and retreatment outcomes after nucleos(t)ide analogue (NUC) therapy discontinuation. Methods: Chronic hepatitis B patients discontinuing NUC were prospectively enrolled. Viral and host predictors, including HBsAg, anti-HBc, the single nucleotide polymorphisms of NTCP (rs2296651), CTLA4 (rs231775), rs3077 (HLA-DPA1), and rs9277535 (HLA-DPB1), and post-therapy predictors were investigated...
January 2, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29300184/correlations-between-contouring-similarity-metrics-and-simulated-treatment-outcome-for-prostate-radiotherapy
#8
Dale Roach, Michael G Jameson, Jason A Dowling, Martin Andrew Ebert, Peter B Greer, Angel M Kennedy, Sandie Watt, Lois C Holloway
Many similarity metrics exist for inter-observer contouring variation studies, however no correlation between metric choice and prostate cancer radiotherapy dosimetry has been explored. These correlations were investigated in this study. Two separate trials were undertaken, the first a thirty-five patient cohort with three observers, the second a five patient dataset with ten observers. Clinical and planning target volumes (CTV and PTV), rectum, and bladder were independently contoured by all observers in each trial...
January 4, 2018: Physics in Medicine and Biology
https://www.readbyqxmd.com/read/29290974/sodium-taurocholate-cotransporting-polypeptide-ntcp-deficiency-identification-of-a-novel-slc10a1-mutation-in-two-unrelated-infants-presenting-with-neonatal-indirect-hyperbilirubinemia-and-remarkable-hypercholanemia
#9
Jian-Wu Qiu, Mei Deng, Ying Cheng, Raza-Muhammad Atif, Wei-Xia Lin, Li Guo, Hua Li, Yuan-Zong Song
Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29285260/genetic-variations-of-ntcp-are-associated-with-susceptibility-to-hbv-infection-and-related-hepatocellular-carcinoma
#10
Peng Wang, Ruidong Mo, Rongtao Lai, Yumin Xu, Jie Lu, Gangde Zhao, Yuhan Liu, Zhujun Cao, Xiaolin Wang, Ziqiang Li, Lanyi Lin, Huijuan Zhou, Wei Cai, Hui Wang, Shisan Bao, Xiaogang Xiang, Qing Xie
Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29273725/functional-shift-with-maintained-regenerative-potential-following-portal-vein-ligation
#11
Tibor Kovács, Domokos Máthé, András Fülöp, Katalin Jemnitz, Attila Bátai-Konczos, Zsuzsanna Veres, György Török, Dániel Sándor Veres, Ildikó Horváth, Krisztián Szigeti, László Homolya, Attila Szijártó
Selective portal vein ligation (PVL) allows the two-stage surgical resection of primarily unresectable liver tumours by generating the atrophy and hypertrophy of portally ligated (LL) and non-ligated lobes (NLL), respectively. To evaluate critically important underlying functional alterations, present study characterised in vitro and vivo liver function in male Wistar rats (n = 106; 210-250 g) before, and 24/48/72/168/336 h after PVL. Lobe weights and volumes by magnetic resonance imaging confirmed the atrophy-hypertrophy complex...
December 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29260740/-hepatitis-c-can-be-cured-will-hepatitis-b-become-next
#12
V P Chulanov, A P Zueva, D S Kostyushev, S A Brezgin, E V Volchkova, V V Maleyev
Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called 'functional cure' is a very rare event...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/29249528/critical-appraisal-of-the-risk-of-secondary-cancer-induction-from-breast-radiation-therapy-with-volumetric-modulated-arc-therapy-relative-to-3d-conformal-therapy
#13
Antonella Fogliata, Fiorenza De Rose, Davide Franceschini, Antonella Stravato, Jan Seppälä, Marta Scorsetti, Luca Cozzi
PURPOSE: To evaluate the excess absolute risk (EAR) comparing volumetric modulated arc therapy (VMAT) and 3-dimensional (3D) conformal radiation therapy (CRT) in breast cancer radiation therapy treatment. METHODS AND MATERIALS: Two VMAT arrangements (VMAT_tang and VMAT_full, i.e. partial arcs with and without a sector of 0 Monitor Unit, respectively) and a 3D CRT (field-in-field [FinF]) plan were calculated with an accurate dose calculation algorithm, Acuros, in 20 patients presenting with early-stage breast cancer...
October 31, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/29247233/effect-of-s267f-variant-of-ntcp-on-the-patients-with-chronic-hepatitis-b
#14
Hye Won Lee, Hye Jung Park, Bora Jin, Mehrangiz Dezhbord, Do Young Kim, Kwang-Hyub Han, Wang-Shick Ryu, Seungtaek Kim, Sang Hoon Ahn
Sodium taurocholate cotransporting polypeptide (NTCP) was identified as an entry receptor for hepatitis B virus (HBV) infection. The substitution of serine at position 267 of NTCP with phenylalanine (S267F) is an Asian-specific variation that hampers HBV entry in vitro. In this study, we aimed to evaluate the prevalence of S267F polymorphism in Korean patients with chronic hepatitis B (CHB) and its association with disease progression and potential viral evolution in the preS1 domain of HBV. We found that the frequency of the S267F variant of NTCP in CHB patients and controls was 2...
December 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29235094/effects-of-corilagin-on-alleviating-cholestasis-via-fxr-associated-pathways-in-vitro-and-in-vivo
#15
Fan Yang, Yao Wang, Gang Li, Juan Xue, Zhi-Lin Chen, Feng Jin, Lei Luo, Xuan Zhou, Qian Ma, Xin Cai, Hua-Rong Li, Lei Zhao
BACKGROUND AND PURPOSE: This aim of this study was to investigate the effects of corilagin on alleviating intrahepatic cholestasis by regulating liver FXR (farnesoid X receptor)-associated pathways in vitro and in vivo. EXPERIMENTAL APPROACH: Cellular and animal models were treated with different concentrations of corilagin. In the cellular experiments, FXR expression was up-regulated by either lentiviral transduction or GW4064 treatment and down-regulated by either siRNA technology or treatment with guggulsterones...
December 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29216213/a-multi-scale-spatial-model-of-hepatitis-b-viral-dynamics
#16
Quentin Cangelosi, Shawn A Means, Harvey Ho
Chronic hepatitis B viral infection (HBV) afflicts around 250 million individuals globally and few options for treatment exist. Once infected, the virus entrenches itself in the liver with a notoriously resilient colonisation of viral DNA (covalently-closed circular DNA, cccDNA). The majority of infections are cleared, yet we do not understand why 5% of adult immune responses fail leading to the chronic state with its collateral morbid effects such as cirrhosis and eventual hepatic carcinoma. The liver environment exhibits particularly complex spatial structures for metabolic processing and corresponding distributions of nutrients and transporters that may influence successful HBV entrenchment...
2017: PloS One
https://www.readbyqxmd.com/read/29212823/quantitative-expression-of-hepatobiliary-transporters-and-functional-uptake-of-substrates-in-hepatic-2d-sandwich-cultures-a-comparative-evaluation-of-upcyte-and-primary-human-hepatocytes
#17
Michelle Schaefer, Gaku Morinaga, Akiko Matsui, Gerhard Schanzle, Daniel Bischoff, Roderich D Sussmuth
Deficient functional expression of drug transporters incapacitates most hepatic cell lines as reliable tool for evaluating transporter-mediated drug-drug interactions. Recently, genetically-modified cells, referred to as upcyte hepatocytes, have emerged as an expandable, non‑cancerous source of human hepatic cells. Herein, we quantified mRNA and protein levels of key hepatobiliary transporters and assessed associated uptake activity in short- and long-term cultures of upcyte human hepatocytes (UHH), in comparison to cryopreserved primary human hepatocytes (cPHH)...
December 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29205714/genetic-variants-in-ntcp-exon-gene-are-associated-with-hbv-infection-status-in-a-chinese-han-population
#18
Wennan Wu, Yongbin Zeng, Jinpiao Lin, Yingying Wu, Tianbin Chen, Zhen Xun, Qishui Ou
OBJECTIVE: Sodium taurocholate co-transporting polypeptide (NTCP) plays an important role in the enterohepatic circulation of bile acids. Recently, NTCP was identified as a hepatitis B virus (HBV) receptor. The aim of this study is to investigate the association of NTCP polymorphisms with HBV clinical outcomes and investigate the relationship between NTCP polymorphisms and the serum bile acid level in Chinese Han population. METHODS: The single nucleotide polymorphisms (SNPs), rs2296651 and rs4646285, were genotyped in 1619 Chinese Han individuals...
December 4, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/29202514/glycyrrhetic-acid-derivative-ty501-protects-against-lithocholic-acid-induced-cholestasis
#19
Xuemin Zheng, Shichao Zhu, Zhixing Zhou, Wei Liu, Weiren Xu
The aim of the study is to investigate the protective effects of TY501 against LCA-induced cholestasis in mice and to explore the potential mechanisms. It was demonstrated that TY501(5, 15 or 45 mg/kg, i.g.) can markedly reduced the level of ALT, AST and ALP which increased by LCA treatment. Meanwhile, TY501 also lowered total bile acids, total bilirubin and total cholesterol levels in serum. Furthermore, TY501 can protect HepG2 cell cultures from LCA-induced cytotoxicity. RT-PCR and Western Blot analysis showed that TY501 recovered the expression of BSEP, MRP2 and NTCP which were down-regulated by LCA...
December 4, 2017: Drug Research
https://www.readbyqxmd.com/read/29198389/cumulative-dose-of-radiation-therapy-of-hepatocellular-carcinoma-patients-and-its-deterministic-relation-to-radiation-induced-liver-disease
#20
Pu Huang, Gang Yu, Daniel S Kapp, Xue-Feng Bian, Chang-Sheng Ma, Hong-Sheng Li, Jin-Hu Chen, Yue-Qiang Liang, Yang Zhang, Shao-Hua Qin, Yao-Qin Xie, Yong Yang, Yong Yin, Lei Xing, Deng-Wang Li
This study aimed to investigate the relationship between dose and radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) receiving 3-dimensional conformal radiotherapy (3DCRT). Twenty-three patients with HCC who received conventional fractionated 3DCRT, including 7 who were diagnosed with classic RILD, were enrolled in this retrospective investigation. Cone-beam computed tomography (CBCT) scans were acquired at the time of treatment for each patient. The beams from each patient's treatment plan were applied to each pretreatment CBCT (the modified CBCT or mCBCT) to construct the delivered dose distribution of the day considering inter-treatment anatomy changes...
November 29, 2017: Medical Dosimetry: Official Journal of the American Association of Medical Dosimetrists
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