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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/27903597/impact-of-organic-cation-transporters-oct-slc22a-on-differential-diagnosis-of-intrahepatic-lesions
#1
Michele Visentin, Belle V van Rosmalen, Christian Hiller, Matthanja Bieze, Lia Hofstetter, Joanne Verheij, Gerd A Kullak-Ublick, Hermann Koepsell, Saffire Sks Phoa, Ikumi Tamai, Roelof J Bennink, Thomas M van Gulik, Bruno Stieger
Positron emission tomography (PET) using the cationic compound [(18)F]fluoromethylcholine (FCH) enhances the sensitivity for non-invasive classification of hepatic tumours due to peculiar patterns of accumulation. The underlying transporters are not known. We aim to identify the carriers mediating uptake of FCH in liver and to correlate their expression pattern with PET intrahepatic signal distribution to clarify the role of membrane transporters in FCH accumulation. FCH transport was characterized in cells overexpressing organic cation transporters (OCTs)...
November 30, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27895114/in-vitro-and-clinical-evaluations-of-the-drug-drug-interaction-potential-of-a-metabotropic-glutamate-2-3-receptor-agonist-prodrug-at-pept1
#2
Y Anne Pak, Amanda J Long, William F Annes, Jennifer W Witcher, Mary Pat Knadler, Mosun A Ayan-Oshodi, Malcolm I Mitchell, Phillip Leese, Kathleen M Hillgren
Despite PEPT1 being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 μM, while the active moiety (LY404039) is not a PEPT1 substrate...
November 28, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27895113/age-dependent-absolute-abundance-of-hepatic-carboxylesterases-ces1-and-ces2-by-lc-ms-ms-proteomics-application-to-pbpk-modeling-of-oseltamivir-in-vivo-pharmacokinetics-in-infants
#3
Mikael Boberg, Marc Vrana, Aanchal Mehrotra, Robin E Pearce, Andrea Gaedigk, Deepak Kumar Bhatt, J Steven Leeder, Bhagwat Prasad
The age-dependent absolute protein abundance of carboxylesterase 1 and 2 (CES1 and CES2) in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by LC-MS/MS proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards...
November 28, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27895112/hepatic-dipeptidyl-peptidase-4-controls-pharmacokinetics-of-vildagliptin-in-vivo
#4
Mitsutoshi Asakura, Tatsuki Fukami, Miki Nakajima, Hideaki Fujii, Koichiro Atsuda, Tomoo Itoh, Ryoichi Fujiwara
The major metabolic pathway of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice co-administered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice...
November 28, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27872146/organic-anion-transporter-2-oat2-an-enigmatic-human-solute-carrier
#5
Hong Shen, Yurong Lai, A David Rodrigues
As a member of the solute carrier 22A (SLC22A) family, OAT2 (SLC22A7) is emerging as an important drug transporter because of its expression in both the liver and kidney, two major eliminating organs, and its ability to transport not only a wide variety of xenobiotics, but also numerous physiologically important endogenous compounds, like creatinine and guanosine 3,5-cyclic monophosphate (cGMP). However, OAT2 has received relatively little attention when compared to other OATs and solute carriers (SLCs) like organic cation transporters, sodium-dependent taurocholate co-transporting polypeptide, multidrug and toxin extrusion proteins, and organic anion-transporting polypeptides...
November 21, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27856528/in-vivo-hepatic-enhancer-elements-in-the-human-abcg2-locus
#6
Rachel J Eclov, Mee J Kim, Robin P Smith, Xiaomin Liang, Nadav Ahituv, Deanna L Kroetz
ABCG2 encodes the mitoxantrone resistance protein (MXR, BCRP), an ATP-binding cassette (ABC) efflux membrane transporter. Computational analysis of the ~300 kb region of DNA surrounding ABCG2 (chr4:88911376-89220011, hg19) identified 30 regions with potential cis-regulatory capabilities. These putative regulatory regions were tested for their enhancer and suppressor activity in a human liver cell line using luciferase reporter assays. The in vitro enhancer and suppressor assays identified four regions that decreased gene expression and five regions that increased expression >1...
November 17, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27856527/role-of-glucocorticoid-receptor-and-pregnane-x-receptor-in-dexamethasone-induction-of-rat-hepatic-aryl-hydrocarbon-receptor-nuclear-translocator-and-nadph-cytochrome-p450-oxidoreductase
#7
Sarah R Hunter, Alex Vonk, Anne K Mullen Grey, David S Riddick
The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), as the AHR's heterodimerization partner, and NADPH-cytochrome P450 oxidoreductase (POR), as the key electron donor for all microsomal P450s, are independent and indispensable components in the adaptive and toxic responses to polycyclic aromatic hydrocarbons. Expression of both ARNT and POR in rat liver is induced by dexamethasone (DEX), a synthetic glucocorticoid known to activate both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR)...
November 16, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27856526/extrapolation-of-elementary-rate-constants-of-p-glycoprotein-mediated-transport-from-mdckii-hmdr1-to-caco-2-cells
#8
Zhou Meng, Harma Ellens, Joe Bentz
The best parameters for incorporation into mechanistic PBPK models for transporters are system independent kinetic parameters and active (not total) transporter levels. Previously, we determined the elementary rate constants for P-gp mediated transport (on- and off- rate constants from membrane to P-gp binding pocket and efflux rate constant into apical chamber) using the structural mass action kinetic model in confluent MDCKII-hMDR1-NKI cell monolayers. In the present work, we extended the kinetic analysis to Caco-2 cells for the first time and showed that the elementary rate constants are very similar compared to MDCKII-hMDR1-NKI cells, suggesting they primarily depend on the interaction of the compound with P-gp and are therefore mostly independent of the in vitro system used...
November 16, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27856525/microvilli-morphology-can-affect-efflux-active-p-glycoprotein-in-confluent-mdckii-nki_hmdr1-and-caco-2-cell-monolayers
#9
Zhou Meng, Sylvain Le Marchand, Deep Agnani, Matt Szapacs, Harma Ellens, Joe Bentz
From fits of drug transport kinetics across confluent MDCKII-hMDR1-NKI and Caco-2 cell monolayers we estimated the levels of efflux active P-glycoprotein (P-gp) in these two cell lines (companion paper, Meng at el., 2016a). In the present work, we compared the efflux active P-gp number to the total P-gp level, using LC/MSMS, and showed that in Caco-2 cells total P-gp is about 10-fold greater than efflux active P-gp, while in MDCKII-hMDR1-NKI cells these values are within 2-fold. We further visualized the microvilli in MDCKII-hMDR1-NKI and Caco-2 cells using three-dimensional structured illumination super-resolution microscopy and found that the microvilli in Caco-2 cells are taller and more densely packed than those in MDCK-NKI-hMDR1 cells...
November 16, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27836942/species-differences-in-human-and-rodent-pept2-mediated-transport-of-glycylsarcosine-and-cefadroxil-in-pichia-pastoris-transformants
#10
Feifeng Song, Yongjun Hu, Huidi Jiang, David E Smith
The proton-coupled oligopeptide transporter PEPT2 (SLC15A2) plays an important role in the disposition of di/tripeptides and peptide-like drugs in kidney and brain. However, unlike PEPT1 (SLC15A1), there is little information about species differences in the transport of PEPT2-mediated substrates. The purpose of this study was to determine whether PEPT2 exhibited a species-dependent uptake of glycylsarcosine (GlySar) and cefadroxil using yeast Pichia pastoris cells expressing the cDNAs from human, mouse and rat...
November 11, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27836941/target-site-investigation-for-the-plasma-prolactin-response-mechanism-based-pharmacokinetic-pharmacodynamic-analysis-of-risperidone-and-paliperidone-in-the-rat
#11
Shinji Shimizu, Sandra M den Hoedt, Victor Mangas Sanjuan, Sinziana Cristea, Jana K Geuer, Dirk-Jan van den Berg, Robin Hartman, Francisco Bellanti, Elizabeth C M de Lange
In order to understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semi-physiologically-based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). A microdialysis study in rats was performed to obtain detailed plasma, brain extracellular fluid (brainECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-gp functioning on brain distribution, experiments were performed in absence or presence of the P-glycoprotein (P-gp) inhibitor tariquidar (TQD)...
November 11, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27821437/curcumin-piperine-and-capsaicin-a-comparative-study-of-spice-mediated-inhibition-of-human-cytochrome-p450-isozyme-activities
#12
Suhaili Shamsi, Huong Tran, Renee Siok Jin Tan, Zee Jian Tan, Lee Yong Lim
Inhibition of the cytochrome P450 (CYP) enzymes has been shown to enhance the metabolism of drugs that are CYP substrates, and to consequently alter their pharmacokinetic profiles. Curcumin (CUR), piperine (PIP) and capsaicin (CAP) are spice components (SC) that inhibit the activities of a range of CYP enzymes, but the selection of which SC to be prioritised for further development as adjuvant will depend on the ranking order of inhibitory potential of the SCs on specific CYP isozymes. This paper aimed to utilise common human recombinant enzyme platforms to provide a comparative evaluation of the inhibitory activities of CUR, PIP and CAP on the principal drug-metabolising CYP enzymes...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27821436/histone-h3-lysine-4-trimethylation-h3k4me3-lysine-27-trimethylation-h3k27me3-and-lysine-27-acetylation-h3k27ac-contribute-to-the-transcriptional-repression-of-solute-carrier-family-47-member-2-in-renal-cell-carcinoma
#13
Qinqin Yu, Yanqing Liu, Xiaoli Zheng, Qianying Zhu, Zhuowei Shen, Hua Wang, Huadong He, Nengming Lin, Huidi Jiang, Lushan Yu, Su Zeng
In recent years, finding effective biomarkers for identifying early stage cancer and predicating prognosis is crucial for renal cell carcinoma (RCC) diagnosis and treatment. In this study, a dramatic decrease of the solute carrier family 47 member 2 (SLC47A2) mRNA in RCC comparing with the paired adjacent non-tumor tissues from patients at low TNM stage was observed. Thus, patients with SLC47A2 transcriptional repression are susceptible to RCC. Little is known about the regulation mechanism of SLC47A2. We found that it was a bivalent gene which was enriched with both histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 trimethylation (H3K27me3)...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27821435/what-can-be-learned-from-recent-new-drug-applications-a-systematic-review-of-drug-interaction-data-for-drugs-approved-by-the-u-s-fda-in-2015
#14
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow-up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, PK, and DDI data available in the 33 NDAs and 12 BLAs approved by the FDA in 2015, using the University of Washington Drug Interaction Database©, and to highlight the significant findings. All of the NDAs were well-characterized with regard to drug metabolism, transport, and/or organ impairment, and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one DME or transporter...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27803021/interaction-of-2-4-diaminopyrimidine-containing-drugs-including-fedratinib-and-trimethoprim-with-thiamine-transporters
#15
Marilyn Giacomini, Jia Hao, Xiaomin Liang, Jayaraman Chandrasekhar, Jolyn Twelves, J Andrew Whitney, Eve-Irene Lepist, Adrian S Ray
Inhibition of thiamine transporters has been proposed as a putative mechanism for the observation of Wernicke's encephalopathy and subsequent termination of clinical development of fedratinib, a Janus Kinase inhibitor (JAKi). This study aimed to determine the potential for other JAKi to inhibit thiamine transport using Caco-2 and thiamine transporter (THTR) over-expressing cells and to better elucidate the structural basis for interacting with THTR. Only JAKi containing a 2,4-diaminopyrimidine were observed to inhibit thiamine transporters...
November 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27784718/clearance-prediction-of-targeted-covalent-inhibitors-by-in-vitro-in-vivo-extrapolation-of-hepatic-and-extrahepatic-clearance-mechanisms
#16
Louis Leung, Xin Yang, Timothy J Strelevitz, Justin Montgomery, Matthew F Brown, Michael A Zientek, Christopher Banfield, Adam M Gilbert, Atli Thorarensen, Martin E Dowty
The concept of target-specific covalent enzyme inhibitors appears attractive from both an efficacy and selectivity viewpoint considering the potential for enhanced biochemical efficiency associated with an irreversible mechanism. Aside from potential safety concerns, clearance prediction of covalent inhibitors represents a unique challenge due to the inclusion of nontraditional metabolic pathways of direct conjugation with glutathione (GSH) or via glutathione S-transferase (GST)-mediated processes. In this paper, a novel pharmacokinetic algorithm was developed using a series of Pfizer kinase selective acrylamide covalent inhibitors based on their in vitro-in vivo extrapolation of systemic clearance in rats...
October 26, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27780835/developmental-changes-in-hepatic-oct1-protein-expression-from-neonates-to-children
#17
David Hahn, Chie Emoto, Alexander A Vinks, Tsuyoshi Fukuda
Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinically-important drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Presently, knowledge of OCT1 protein expression in children is very limited, especially among neonates and small infants. Here, we report on the characterization of OCT1 protein expression in neonatal, infant and pediatric liver samples performed by Immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal day 1 - 2...
October 25, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27780834/stable-overexpression-of-the-constitutive-androstane-receptor-reduces-the-requirement-for-culture-with-dimethyl-sulfoxide-for-high-drug-metabolism-in-heparg-cells
#18
Vincent A van der Mark, D Rudi de Waart, Valery Shevchenko, Ronald P J Oude Elferink, Robert A F M Chamuleau, Ruurdtje Hoekstra
Dimethyl sulfoxide (DMSO) induces cellular differentiation and expression of drug metabolic enzymes in the human liver cell line HepaRG. However, DMSO also induces cell death and interferes with cellular activities. The aim of this study was to examine if overexpression of the constitutive androstane receptor (CAR, NR1I3), the nuclear receptor controlling various drug metabolism genes, would sufficiently promote differentiation and drug metabolism in HepaRG cells, optionally without using DMSO. By stable lentiviral overexpression of CAR, HepaRG cultures were less affected by DMSO in total protein content and obtained increased resistance to acetaminophen- and amiodarone-induced cell death...
October 25, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27777246/managing-the-risk-of-cyp3a-induction-in-drug-development-a-strategic-approach
#19
Barry C Jones, Helen Rollison, Susanne A Johansson, Kajsa P Kanebratt, Craig Lambert, Karthick Vishwanathan, Tommy B Andersson
Induction of cytochrome P450 (CYP) can impact the efficacy and safety of a drug molecule upon multiple dosing of co-administered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of CYP induction are related to this enzyme. However, the in vitro evaluation of induction is applicable to other CYP enzymes but the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the pre-clinical phase, compounds are screened using PXR reporter gene assay and, if necessary, structure-activity relationships (SAR) are developed...
October 24, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27756789/application-of-mice-humanised-for-cytochrome-p450-cyp2d6-to-the-study-of-tamoxifen-metabolism-and-drug-drug-interaction-with-antidepressants
#20
A Kenneth MacLeod, Lesley A McLaughlin, Colin J Henderson, C Roland Wolf
Tamoxifen is an oestrogen-receptor (ER) antagonist used in the treatment of breast cancer. It is a pro-drug, converted by several P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Anti-depressants (ADs), which are often co-prescribed to patients receiving tamoxifen, are also metabolised by CYP2D6 and evidence suggests that a drug-drug interaction (DDI) between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation...
October 18, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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