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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/28069721/specific-inhibition-of-the-distribution-of-lobeglitazone-to-the-liver-by-atorvastatin-in-rats-evidence-for-an-roatp1b2-mediated-interaction-in-hepatic-transport
#1
Chang-Soon Yim, Yoo-Seong Jeong, Song-Yi Lee, Wonji Pyeon, Heon-Min Ryu, Jong-Hwa Lee, Kyeong-Ryoon Lee, Han-Joo Maeng, Suk-Jae Chung
CYP enzymes and hOATP1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new PPARγ agonist. Atorvastatin (ATV), a substrate for CYP3A and hOATP1B1, is likely to be co-administered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was IV-administered with ATV, the systemic clearance (CL; 2.67 ± 0.63 mL/min/kg) and volume of distribution at steady-state (Vss; 289 ± 20 mL/kg) for LB remained unchanged, compared to those of LB without ATV (CL, 2...
January 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28069720/pregnancy-increases-the-renal-secretion-of-n1-methylnicotinamide-an-endogenous-probe-for-renal-cation-transporters-in-patients-prescribed-metformin
#2
Mackenzie C Bergagnini-Kolev, Mary F Hebert, Thomas R Easterling, Yvonne S Lin
N1-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1 and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes and polycystic ovarian syndrome (PCOS) during early-, mid-, and late-pregnancy (n = 34 visits) and postpartum (n=14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry...
January 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28062543/multiple-slc-and-abc-transporters-contribute-to-the-placental-transfer-of-entecavir
#3
Zhiyuan Ma, Xi Yang, Ting Jiang, Mengru Bai, Caihong Zheng, Su Zeng, Dongli Sun, Huidi Jiang
Entecavir (ETV), a nucleoside analogue with high efficacy against hepatitis B virus, is recommended as a first-line antiviral drug for the treatment of chronic hepatitis B. However, scant information is available on the use of ETV in pregnancy. To better understand the safety of ETV in pregnant women, we aimed to demonstrate whether ETV could permeate placental barrier and the underlying mechanism. Our study showed that small amount of ETV could permeate across placenta in mice. ETV accumulation in activated or non-activated BeWo cells (treated with or without forskolin) was sharply reduced in the presence of 100 μM of adenosine, cytidine and in Na+ free medium, indicating that nucleoside transporters possibly mediate the uptake of ETV...
January 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28062542/phenobarbital-treatment-at-a-neonatal-age-results-in-decreased-efficacy-of-omeprazole-in-adult-mice
#4
Yun-Chen Tien, Stephanie C Piekos, Chad Pope, Xiao-Bo Zhong
Drug-drug interactions (DDIs) occur when the action of one drug interferes with or alters the activity of another drug taken concomitantly. This can lead to decreased drug efficacy or increased toxicity. Because of DDIs, physicians in the clinical practice attempt to avoid potential interactions when multiple drugs are co-administrated, however there is still a large knowledge gap in understanding how drugs taken in the past can contribute to DDIs in the future. The goal of this study is to investigate the consequence of neonatal drug exposure on efficacy of other drugs administered to adult life...
January 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28062541/evaluation-of-a-novel-renewable-hepatic-cell-model-for-prediction-of-clinical-cyp3a4-induction-using-a-correlation-based-ris-approach
#5
Rongjun Zuo, Feng Li, Sweta Parikh, Li Cao, Kirsten L Cooper, Yulong Hong, Jin Liu, Ronald A Faris, Daochuan Li, Hongbing Wang
Metabolism enzyme induction-mediated drug-drug interactions need to be carefully characterized in vitro for drug candidates in order to predict in vivo outcomes of safety risk and therapeutic efficiency. Currently, both the FDA and EMA recommend using primary human hepatocytes as the "Gold Standard" in vitro test system for studying the induction potential of candidate drugs on cytochrome P450 (CYP), CYP3A4, CYP1A2, and CYP2B6. However, primary human hepatocytes are known to bear inherent limitations such as limited supply and large lot-to-lot variations which result in an experimental burden to qualify new lots...
January 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28053220/application-of-static-modeling-in-the-prediction-of-in-vivo-drug-drug-interactions-between-rivaroxaban-and-anti-arrhythmic-agents-based-on-in-vitro-inhibition-studies
#6
Eleanor Jing Yi Cheong, Janice Jia Ni Goh, Yanjun Hong, Gopalakrishnan Venkatesan, Yuanjie Liu, Gigi Ngar Chee Chiu, Pipin Kojodjojo, Eric Chun Yong Chan
Rivaroxaban, a direct Factor Xa inhibitor, is indicated for stroke prevention in non-valvular atrial fibrillation (AF). Studies have revealed that the clearance of rivaroxaban is largely attributed to CYP3A4, CYP2J2 metabolism and P-gp efflux pathways. Amiodarone and dronedarone are anti-arrhythmic agents employed in AF management. Amiodarone, dronedarone and their major metabolites, N-desethylamiodarone (NDEA) and N-desbutyldronedarone (NDBD) demonstrate inhibitory effects on CYP3A4 and CYP2J2 with FDA recommended probe substrates...
January 4, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28049636/verification-of-a-maternal-fetal-physiologically-based-pharmacokinetic-model-for-passive-placental-permeability-drugs
#7
Zufei Zhang, Jashvant D Unadkat
Fetal exposure to drugs cannot be readily estimated from single time point cord blood sampling at the time of delivery. Therefore, we developed a physiologically-based pharmacokinetic (PBPK) model to estimate fetal drug exposure throughout pregnancy. Here we report verification of this novel maternal-fetal physiologically-based pharmacokinetic (m-f-PBPK) model for drugs that passively diffuse across the placenta and are not metabolized/transported there. Our recently built m-f-PBPK model was populated with gestational age-dependent changes in maternal drug disposition and maternal-fetal physiology...
January 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28031430/metabolic-disposition-of-luteolin-is-mediated-by-the-interplay-of-udp-glucuronosyltransferases-and-catechol-o-methyltransferases-in-rats
#8
Liping Wang, Qingwei Chen, Lijun Zhu, Qiang Li, Xuejun Zeng, Linlin Lu, Ming Hu, Xinchun Wang, Zhongqiu Liu
Luteolin partialy exerts its biological effects via its metabolites catalyzed by UDP-glucuronosyltransferases (UGTs) and catechol-O-methyltransferases (COMTs). However, the interplay of UGTs and COMTs in mediating luteolin disposition has not been well clarified. In this study, we investigated the glucuronidation and methylation pathways of luteolin mediated by the interplay of UGTs and COMTs in vivo and in vitro A total of nine luteolin metabolites were detected in rat plasma and bile by liquid chromatography - tandem mass spectrometry, namely, three glucuronides, two methylated metabolites, and four methylated glucuronides...
December 28, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27993930/absorption-metabolism-and-excretion-of-a-novel-bcl-2-inhibitor-venetoclax-in-humans
#9
Hong Liu, Melissa J Michmerhuizen, Yanbin Lao, Katty Wan, Ahmed Hamed Salem, James Sawicki, Michael Serby, Srirajan Vaidyanathan, Shekman L Wong, Suresh Agarwal, Martin Dunbar, Jens Sydor, Sonia Maria de Morais, Anthony J Lee
Venetoclax (also known as ABT-199) is a B-cell lymphoma-2 (Bcl-2) family protein inhibitor and is currently in clinical development for the treatment of chronic lymphocytic leukaemia (CLL) and other hematological malignancies. The objective of this study was to characterize the absorption, metabolism, and excretion of venetoclax in humans. Following a single oral dose of 200 mg (100 μ - Ci) of [(14)C]venetoclax to four healthy volunteers, recovery of total radioactive dose was 100% (± 5%), with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0...
December 19, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27974382/functional-characterization-of-34-cyp2a6-allelic-variants-by-assessment-of-nicotine-c-oxidation-and-coumarin-7-hydroxylation-activities
#10
Hiroki Hosono, Masaki Kumondai, Masamitsu Maekawa, Hiroaki Yamaguchi, Nariyasu Mano, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka
Cytochrome P450 2A6 (CYP2A6) is one of the enzymes responsible for the metabolism of therapeutic drugs and tobacco components, such as nicotine, 4-methylnitrosoamino-1-(3-pyridyl)-1-butanone, and N-nitrosodiethylamine. Genetic polymorphisms in CYP2A6 are associated with individual variation in smoking behavior, drug toxicity, and the risk of developing several cancers. In this study, we conducted an in vitro analysis of 34 allelic variants of CYP2A6 using nicotine and coumarin as representative CYP2A6 substrates...
December 14, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27974381/difference-in-mechanism-based-inhibition-of-cytochrome-p450-3a4-and-3a5-by-a-series-of-fluoroquinolone-antibacterial-agents
#11
Akiko Watanabe, Hideo Takakusa, Takako Kimura, Shin-Ichi Inoue, Hiroyuki Kusuhara, Osamu Ando
A series of fluoroquinolone antibacterial compounds were found to be irreversible (compounds 1 - 5) and quasi-irreversible (compounds 6 - 9) inhibitors of cytochrome P450 3A4 (CYP3A4). The purpose of this study was to evaluate their mechanism-based inhibition (MBI) potency against CYP3A5. Compounds 1 - 5 were also irreversible inhibitors of CYP3A5, whereas compounds 6 - 9 showed neither irreversible nor quasi-irreversible inhibition of CYP3A5. Compounds 6 and 8 did not form a metabolite-intermediate (MI) complex with the heme of CYP3A5 during incubation...
December 14, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27974380/incorporation-of-zolpidem-into-hair-and-its-distribution-after-a-single-administration
#12
Noriaki Shima, Keiko Sasaki, Tooru Kamata, Shuntaro Matsuta, Misato Wada, Hidenao Kakehashi, Shihoko Nakano, Hiroe Kamata, Hiroshi Nishioka, Takako Sato, Hitoshi Tsuchihashi, Akihiro Miki, Munehiro Katagi
In order to obtain fundamental information on the drug incorporation into hair, time-course changes in drug distribution along single-strand hair were observed following a single oral administration of zolpidem (ZP), one of the most frequently-used hypnotics. Quantitative sectional hair analyses of 1-mm segments were performed for each single-strand hair using a validated liquid chromatography-tandem mass spectrometry procedure. ZP was detected in all specimens plucked at 10 and 24 hours after a single dose, and the distribution ranged over the whole hair root (4-5 mm in length)...
December 14, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27927688/stereoselective-pharmacokinetics-and-chiral-inversion-of-ibuprofen-in-adjuvant-induced-arthritic-rats
#13
Hiroyuki Ikuta, Atsushi Kawase, Masahiro Iwaki
2-Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs are commonly used in racemic mixtures (rac) for clinical use. 2-APA undergo unidirectional chiral inversion of the in vivo inactive R-enantiomer to the active S-enantiomer. Inflammation causes the reduction of metabolic activities of drug-metabolizing enzymes such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase. However, it is unclear whether inflammation affects the stereoselective pharmacokinetics and chiral inversion of 2-APA such as ibuprofen (IB)...
December 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27934638/comparative-evaluation-of-dehydroepiandrosterone-sulfate-dheas-potential-to-predict-hepatic-oatp-transporter-based-drug-drug-interactions
#14
Kei Nishizawa, Takeo Nakanishi, Ikumi Tamai
Pharmacokinetic drug-drug interactions (DDIs) on hepatic organic anion transporting polypeptides (OATPs) are important clinical issues. Previously we reported that plasma dehydroepiandrosterone sulfate (DHEAS) could serve as an endogenous probe to predict OATP-based DDIs in monkeys using rifampicin as an OATP inhibitor. However, since the contribution of hepatic OATPs to the changes of plasma DHEAS by rifampicin remains unclear, here, we evaluated by an in vivo pharmacokinetic study. Since plasma DHEAS concentrations were unexpectedly low in our rat model, disposition of externally administered DHEAS was evaluated...
December 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27934637/management-of-rodent-populations-by-anticoagulant-rodenticides-toward-third-generation-anticoagulant-rodenticides
#15
Marlene Damin-Pernik, Bernadette Espana, Sebastien Lefebvre, Isabelle Fourel, Herve Caruel, Etienne Benoit, Virginie Lattard
Second-generation anticoagulant rodenticides (SGARs) have been used since the 1980s for pest management. They are highly efficient even in warfarin-resistant rodents. Nevertheless, because of their tissue persistence, non-target poisoning by SGARs is commonly described in wildlife. Due to this major problem, a new generation of anticoagulants must be developed to limit this risk. This study proposes a method of developing a new generation of anticoagulant rodenticides by re-visiting the old SGARs based on the concept of stereochemistry...
December 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27934636/impact-of-probe-substrate-selection-on-cytochrome-p450-reaction-phenotyping-using-relative-activity-factor
#16
Yin Fai Amy Siu, Weidong George Lai
Accurately assessing the contribution of cytochrome P450 (CYP) isoforms to overall metabolic clearance is important for prediction of clinical drug-drug interaction (DDI). The relative activity factor (RAF) approach in CYP reaction phenotyping assumes that the interaction between CYP selective probes and testing systems is the same as to drug candidate with those systems. To test this assumption, Intersystem Clearance Ratio (ICR) was created to evaluate the difference in values between RAF-scaled intrinsic clearance (CLint) and measured CLint in human liver microsomes (HLM)...
December 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27934635/metabolism-of-the-mek1-2-inhibitor-pimasertib-involves-a-novel-conjugation-with-phospho-ethanolamine-in-patients-with-solid-tumors
#17
Holger Scheible, Friedrich Kraetzer, Andreas Marx, Andreas Johne, Elmar Wimmer
Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical anti tumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of (14)C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT 01713036). Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine and feces after a single oral dose of (14)C-pimasertib...
December 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27903597/impact-of-organic-cation-transporters-oct-slc22a-on-differential-diagnosis-of-intrahepatic-lesions
#18
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
#19
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
#20
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
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