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Drug Metabolism and Pharmacokinetics

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https://www.readbyqxmd.com/read/28734646/quantitative-prediction-of-therapeutic-antibody-pharmacokinetics-after-intravenous-and-subcutaneous-injection-in-human
#1
Kenta Haraya, Tatsuhiko Tachibana, Junichi Nezu
Prediction of the plasma/serum mAb concentration-time profile in human is important to determine the required dose regime. This study proposes an approach for predicting the plasma/serum mAb concentration-time profile after intravenous and subcutaneous injection in human based on comprehensive analysis of reported pharmacokinetic data. Optimal scaling exponents from cynomolgus monkey to human for CL, Q, Vc, and Vp were estimated as 0.8, 0.75, 1.0, and 0.95, respectively. The estimated exponents were used to predict plasma/serum mAb concentration-time profile in human from pharmacokinetic data in cynomolgus monkey, and the results had reasonable accuracy with symmetric variability of prediction...
May 29, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28587746/corrigendum-to-quantitative-prediction-of-histamine-h1-receptor-occupancy-by-the-sedative-and-non-sedative-antagonists-in-the-human-central-nervous-system-based-on-systemic-exposure-and-preclinical-data-drug-metab-pharmacokinet-32-2017-135-144
#2
Kayoko Kanamitsu, Yoshitane Nozaki, Yoko Nagaya, Yuichi Sugiyama, Hiroyuki Kusuhara
No abstract text is available yet for this article.
May 22, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28736185/effect-of-coa-cl-on-transforming-growth-factor-%C3%AE-1-induced-epithelial-mesenchymal-transition-in-rle-abca3-cells
#3
Masashi Kawami, Junya Deguchi, Ryoko Yumoto, Norikazu Sakakibara, Ikuko Tsukamoto, Ryoji Konishi, Mikihisa Takano
Transforming growth factor (TGF)-β1 has received much attention as a major inducer of epithelial-mesenchymal transition (EMT) in pathological conditions such as cancer and organ fibrosis. In this study, we examined the effect of a novel nucleic acid analog, COA-Cl, on TGF-β1-induced EMT using RLE/Abca3, a cell line having alveolar type II cell-like phenotype. Changes in the cell morphology consistent with EMT were induced by TGF-β1, whereas, this response was suppressed by co-treatment of the cells with COA-Cl...
May 17, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28734645/computational-study-of-the-competitive-binding-of-valproic-acid-glucuronide-and-carbapenem-antibiotics-to-acylpeptide-hydrolase
#4
Takeshi Ishikawa, Hiroki Otaki, Satoshi Mizuta, Masami Kuriyama, Osamu Onomura, Norihide Higuchi, Mihoko N Nakashima, Mikiro Nakashima, Kaname Ohyama
The efficacy of the antiepileptic drug VPA is decreased by co-administered carbapenems (CBPMs). The mechanism of CBPM selective inhibition of acylpeptide hydrolase (APEH) hydrolysis of VPA-glucuronide (VPA-G) to VPA is unclear due to the lack of APEH structural information. Here we performed homology modeling of the three-dimensional structure of APEH and subsequent docking simulations with a modeled structure to understand this mechanism. Docking simulations indicated that four groups of binding structures were involved in the binding of VPA-G, panipenem, and meropenem to APEH, but only one or two binding structures were involved in the binding of meropenem with an open β-lactam ring structure and other antibiotics involving ampicillin...
April 30, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28522025/corrigendum-to-genetic-polymorphism-of-cynomolgus-and-rhesus-macaque-cyp2c9-drug-metab-pharmacokinet-30-2015-130-132
#5
Yasuhiro Uno, Akinori Matsushita, Norie Murayama, Hiroshi Yamazaki
No abstract text is available yet for this article.
June 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28427759/polymorphisms-in-cyp2c8-and-cyp3a5-genes-in-the-nigerian-population
#6
Ayorinde Adehin, Oluseye Oladotun Bolaji, Martin A Kennedy
Polymorphisms in CYP2C8 and CYP3A5 genes have implications for responses elicited by the ingestion of some xenobiotics, the metabolism of which are mediated by these enzymes. CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A5*6 and CYP3A5*7 are a few functionally-relevant variants of these genes which this study provides data for, in the Nigerian population. Blood samples were processed for genomic DNA from 178 unrelated subjects spread across Nigerian ethnicities and screened for these polymorphism through the Sequenom iPLEX MassARRAY platform...
June 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28412023/precise-prediction-of-activators-for-the-human-constitutive-androstane-receptor-using-structure-based-three-dimensional-quantitative-structure-activity-relationship-methods
#7
Harutoshi Kato, Noriyuki Yamaotsu, Norihiko Iwazaki, Shigeaki Okamura, Toshiyuki Kume, Shuichi Hirono
The constitutive androstane receptor (CAR, NR1I3) regulates the expression of numerous drug-metabolizing enzymes and transporters. The upregulation of various enzymes, including CYP2B6, by CAR activators is a critical problem leading to clinically severe drug-drug interactions (DDIs). To date, however, few effective computational approaches for identifying CAR activators exist. In this study, we aimed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict the CAR activating potency of compounds emerging in the drug-discovery process...
June 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28366619/development-of-pharmacophore-based-classification-model%C3%A2-for%C3%A2-activators-of-constitutive-androstane-receptor
#8
Kyungro Lee, Hwan You, Jiwon Choi, Kyoung Tai No
Constitutive androstane receptor (CAR) is predominantly expressed in the liver and is important for regulating drug metabolism and transport. Despite its biological importance, there have been few attempts to develop in silico models to predict the activity of CAR modulated by chemical compounds. The number of in silico studies of CAR may be limited because of CAR's constitutive activity under normal conditions, which makes it difficult to elucidate the key structural features of the interaction between CAR and its ligands...
June 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28365301/species-specificity-profiling-of-rat-and-human-organic-cation-carnitine-transporter-slc22a5-slc22a5-octn2-octn2
#9
Kitti Szabó, Zoltán Nagy, Viktória Juhász, Joseph K Zolnerciks, Attila Csorba, Zoltán Tímár, Éva Molnár, Petra Pádár, William Johnson, Erzsébet Beéry, Péter Krajcsi
The purpose of this study was to characterize the uptake of carnitine, the physiological substrate, and the uptake of 3-(2,2,2-trimethylhydrazinium)propionate, a consensus substrate by rat Octn2 and human OCTN2 transporters as well as to characterize drug-mediated inhibition of l-carnitine uptake by the rat and human orthologs overexpressed in CHO-K1 cells. l-carnitine and 3-(2,2,2-trimethylhydrazinium)propionate were found to be a lower affinity substrate for rat Octn2 (KM = 32.66 ± 5.11 μM and 23.62 ± 4...
June 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28318879/evidences-for-salbutamol-metabolism-by-respiratory-and-liver-cell-lines
#10
Titpawan Nakpheng, Supreedee Songkarak, Tan Suwandecha, Rutthapol Sritharadol, Charisopon Chunhachaichana, Teerapol Srichana
This study aimed to investigate the enantiomeric biotransformation of salbutamol in the human respiratory and liver cells. The cells from the different cell growth cycles were treated with various concentrations of salbutamol sulfate. Salbutamol and its metabolites were analyzed using chiral liquid chromatography and mass spectrometry. There were no metabolites of salbutamol found in the extracellular medium, intracellular, and cell lysate of respiratory cell lines. The S/R ratios of salbutamol were found to be 0...
April 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28318878/insulin-stimulates-transport-of-organic-anion-compounds-mediated-by-organic-anion-transporting-polypeptide-2b1-in-the-human-intestinal-cell-line-caco-2
#11
Taku Kobayashi, Takahiro Koizumi, Masaki Kobayashi, Jiro Ogura, Yuichi Horiuchi, Yuki Kimura, Ayuko Kondo, Ayako Furugen, Katsuya Narumi, Natsuko Takahashi, Ken Iseki
Organic anion transporting polypeptide 2B1 (OATP2B1) is the major uptake transporter in the intestine, and transports various clinically used therapeutic agents. Insulin acts through the insulin receptor in targeted cells, and Rab8A is one of the insulin signaling pathways. The small intestine in humans also expresses insulin receptor and Rab8A. It has been reported that insulin stimulates peptide transporter 1 (PEPT1) expression at the apical membrane and increases uptake of PEPT1 substrates in small intestine epithelial model cells (Caco-2 cells)...
April 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28209435/contribution-of-equilibrative-nucleoside-transporter-ent-2-to-fluorouracil-transport-in-rat-placental-trophoblast-cells
#12
Akinori Takagi, Tomohiro Nishimura, Tomoya Akashi, Masatoshi Tomi, Emi Nakashima
Fluorouracil is used for treatment of breast cancer even in pregnant women, except during fetal organogenesis. The purpose of this study was to clarify the transport mechanism of fluorouracil at the rat placental barrier. Maternal-to-fetal transfer of [(3)H]fluorouracil in rats at gestational day 19.5 was saturable and much higher than that of [(14)C]sucrose. The uptake of [(3)H]fluorouracil was also saturable in rat placental trophoblast TR-TBT 18d-1 cells, which express both equilibrative nucleoside transporter (ENT) 1 and ENT2...
April 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28190756/organic-anion-transporting-polypeptide-oatp-2b1-contributes-to-the-cellular-uptake-of-theaflavin
#13
Ayuko Kondo, Katsuya Narumi, Jiro Ogura, Ai Sasaki, Keisuke Yabe, Taku Kobayashi, Ayako Furugen, Masaki Kobayashi, Ken Iseki
Organic anion-transporting polypeptide (OATP) 2B1 has been reported in the apical membranes of the human small intestinal epithelium, where it contributes to the intestinal absorption of pharmacologically active drugs. To investigate the potential for OATP2B1-mediated drug-food interactions, the effects of several polyphenolic compounds on OATP2B1-mediated estrone-3-sulfate (E3S) transport were studied by using OATP2B1-expressing HEK293 cells. Our results showed that some compounds, especially theaflavin, were strong inhibitors of OATP2B1-mediated E3S uptake...
April 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28190755/quantitative-prediction-of-histamine-h1-receptor-occupancy-by-the-sedative-and-non-sedative-antagonists-in-the-human-central-nervous-system-based-on-systemic-exposure-and-preclinical-data
#14
Kayoko Kanamitsu, Yoshitane Nozaki, Yoko Nagaya, Yuichi Sugiyama, Hiroyuki Kusuhara
Significant histamine H1 receptor occupation in the central nervous system (CNS) is associated with sedation. Here we examined the time profiles of the H1 receptor occupancy (RO) in the CNS using sedative (diphenhydramine and ketotifen) and non-sedative (bepotastine and olopatadine) antagonists at their therapeutic doses by integrating in vitro and animal data. A pharmacokinetic model was constructed to associate plasma concentrations and receptor binding in the brain. Dissociation and association rate constants with the H1 receptor and plasma and brain unbound fractions were determined in vitro...
April 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28139372/in%C3%A2-vitro-ocular-metabolism-and-bioactivation-of-ketoconazole-in-rat-rabbit-and-human
#15
Amanda L Cirello, Jennifer L Dumouchel, Mithat Gunduz, Christine E Dunne, Upendra A Argikar
Oral ketoconazole is clinically administered for treatment of severe cases for fungal keratitis. Pharmacodynamics and efficacy of oral and topical (ocular) ketoconazole have been explored in rabbit. However, metabolism of ketoconazole in the eye in any species is not well explored in any preclinical species or human. An understanding of ocular drug metabolism in the eye is crucial for ocular therapeutics to facilitate the risk assessment and development of potential drug candidates for the clinic. We aimed to investigate the metabolism of ketoconazole in rat, rabbit and human ocular S9 fractions...
April 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28619281/metabolism-of-ko143-an-abcg2-inhibitor
#16
Ke Liu, Junjie Zhu, Yixian Huang, Chaoyue Li, Jie Lu, Madhav Sachar, Song Li, Xiaochao Ma
The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice...
March 6, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28705419/appreciation-to-reviewers-2016
#17
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
February 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28153493/cyp2c76-deficiency-is-embryonic-lethal-in-cynomolgus-macaques-the-potential-role-of-cyp2c76-in-early-embryogenesis
#18
Shuzo Koyama, Koji Fukuda, Sho Watanabe, Akinori Matsushita, Hideaki Tsuchiya, Nahoko Fujinami, Sakae Kohara, Norie Murayama, Masashi Nagano, Hiroshi Yamazaki, Koichiro Fukuzaki, Yasuhiro Uno, Yoshihiko Hosoi
Cynomolgus macaques are an important primate species for drug metabolism studies; however cynomolgus CYP2C76, an important drug-metabolizing enzyme, accounts for drug metabolism differences to humans, so that CYP2C76-null animals might show drug-metabolizing properties more similar to humans. In this study, attempts were made to produce CYP2C76-null animals by assisted reproduction technology. Oocytes and sperm collected from the heterozygotes for the null allele (c.449TG > A) were subjected to intracytoplasmic sperm injection, and the embryos produced were cultured in vitro through the blastocyst stage...
February 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28153492/sex-and-age-dependent-gene-expression-in-human-liver-an-implication-for-drug-metabolizing-enzymes
#19
Yasuhiro Uno, Ryo Takata, Go Kito, Hiroshi Yamazaki, Kazuko Nakagawa, Yusuke Nakamura, Tetsuya Kamataki, Toyomasa Katagiri
Sex and age differences in hepatic expression of drug-metabolizing enzyme genes could cause variations in drug metabolism, but has not been fully elucidated, especially in Asian population. In this study, the global expression of human hepatic genes was analyzed by microarrays in 40 Japanese subjects (27 males and 13 females). Thirty-five sex-biased genes were identified (P < 0.005). Whereas, 60 age-biased genes in two age groups, <60 years and ≥70 years (P < 0.001), were identified in males...
February 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28139373/development-of-caco-2-cells-co-expressing-cyp3a4-and-nadph-cytochrome-p450-reductase-using-a-human-artificial-chromosome-for-the-prediction-of-intestinal-extraction-ratio-of-cyp3a4-substrates
#20
Toru Takenaka, Kanako Kazuki, Naomoto Harada, Jiro Kuze, Masato Chiba, Takahiro Iwao, Tamihide Matsunaga, Satoshi Abe, Mitsuo Oshimura, Yasuhiro Kazuki
The Caco-2 cells co-expressing cytochrome P450 (CYP) 3A4 and NADPH-cytochrome P450 reductase (CPR) were developed using a human artificial chromosome (HAC) vector. The CYP3A4 and CPR genes were cloned into the HAC vector in CHO cells using the Cre-loxP system, and the microcell-mediated chromosome transfer technique was used to transfer the CYP3A4-CPR-HAC vector to Caco-2 cells. After seeding onto semipermeable culture inserts, the CYP3A4-CPR-HAC/Caco-2 cells were found to form tight monolayers, similar to the parental cells, as demonstrated by the high transepithelial electrical resistance (TEER) value and comparable permeability of non-CYP3A4 substrates between parent and CYP3A4-CPR-HAC/Caco-2 cell monolayers...
February 2017: Drug Metabolism and Pharmacokinetics
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