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Drug Metabolism and Pharmacokinetics

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https://www.readbyqxmd.com/read/29759884/assessment-of-induced-cyp3a-activity-in-pregnant-women-using-4%C3%AE-hydroxycholesterol-cholesterol-ratio-as-an-appropriate-metabolic-marker
#1
Andrew HyoungJin Kim, Bora Kim, Su-Jin Rhee, Yujin Lee, Joong Shin Park, Seung Mi Lee, Sun Min Kim, SeungHwan Lee, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho
AIMS: This study was aimed at evaluating changes in CYP3A activity following and during pregnancy by analyzing metabolic markers for CYP3A activity, which can help avoid unnecessary drug exposure and invasive sampling. METHODS: Forty-eight pregnant women and 25 non-pregnant women were enrolled in this study. Plasma and urine samples were collected from the pregnant women during each trimester and from the non-pregnant women for evaluation of metabolic markers for CYP3A activity...
April 25, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29724614/total-hepatocellular-disposition-profiling-of-rosuvastatin-and-pitavastatin-in-sandwich-cultured-human-hepatocytes
#2
Katsuhiro Kanda, Ryosuke Takahashi, Takashi Yoshikado, Yuichi Sugiyama
This study describes the total disposition profiling of rosuvastatin (RSV) and pitavastatin (PTV) using a single systematic procedure called D-PREX (Disposition Profile Exploration) in sandwich-cultured human hepatocytes (SCHH). The biliary excretion fractions of both statins were clearly observed, which were significantly decreased dependent on the concentration of Ko143, an inhibitor for breast cancer resistance protein (BCRP). Ko143 also decreased the basolateral efflux fraction of RSV, whereas that of PTV was not significantly affected...
April 9, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29655914/importance-of-cynomolgus-monkeys-in-development-of-monoclonal-antibody-drugs
#3
REVIEW
Kazuhide Iwasaki, Yasuhiro Uno, Masahiro Uto, Hiroshi Yamazaki
Animal species used in the preclinical studies for development of monoclonal antibody (mAb) drugs are surveyed in this review. Relevant animal species for preclinical studies of mAb candidates are those express desired epitope of mAb candidates. Cynomolgus monkeys cross-react with mAb drugs much higher than other animal species commonly used in preclinical studies such as absorption, distribution, metabolism and excretion (ADME), efficacy, and toxicity studies, for development of new drugs. Moreover, plasma exposure of the mAb drugs in humans is predicted well from the exposure in the monkeys, and the placental transfer of immunoglobulin G (IgG, all the mAb drugs contain IgG) from mother to fetus is similar between humans and the monkeys from a viewpoint of time course and plasma level of IgG transferred...
March 20, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29773500/an-analysis-on-distribution-and-inter-relationships-of-biomarkers-under-rivaroxaban-in-japanese-patients-with-non-valvular-atrial-fibrillation-cvi-aro-1
#4
Shinya Suzuki, Takeshi Yamashita, Hidefumi Kasai, Takayuki Otsuka, Koichi Sagara
Prothrombin time (PT) has been widely used for measuring anticoagulation intensity under rivaroxaban therapy, but precise information has not been well established yet. Consecutive 96 non-valvular atrial fibrillation (NVAF) under rivaroxaban between Jan/June, 2015 were recruited. Serum concentration (SC) and PT with 5 representative reagents available in Japan (Neoplastin Plus®, Thromborel S®, Thrombocheck PT®, Thrombocheck PT Plus®, and Recombiplastin®) at 2-4 hours after (peak) and before intake of rivaroxaban (trough) were measured at outpatient clinic in the cardiovascular institute (CVI ARO study 1)...
March 15, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29759885/terfenadone-is-a-strong-inhibitor-of-cyp2j2-present-in-the-human-liver-and-intestinal-microsomes
#5
Eunyoung Lee, Ju-Hyun Kim, Jong Cheol Shon, Zhexue Wu, Hyun Ji Kim, Minsik Gim, Taeho Lee, Kwang-Hyeon Liu
Cytochrome P450 2J2 (CYP2J2) is involved in the metabolism of drugs, including albendazole, astemizole, ebastine, and endogenous substrates. In a previous study, we used recombinant CYP2J2 and determined whether danazol, hydroxyebastine, telmisartan, and terfenadone inhibited CYP2J2 by using four representative CYP2J2 substrates, namely albendazole, astemizole, ebastine, and terfenadine. In this study, we evaluated the inhibitory potential of these four chemicals on human liver and intestinal microsomes, which are commonly used in a reaction phenotyping study...
March 15, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29703433/points-to-consider-documents-scientific-information-on-the-evaluation-of-genetic-polymorphisms-during-non-clinical-studies-and-phase-i-clinical-trials-in-the-japanese-population
#6
REVIEW
Masahiro Hiratsuka, Noriyasu Hirasawa, Yoshiteru Oshima, Susumu Kodama, Toshio Miyata, Takashi Dan, Hiroyuki Takatoku, Hideaki Kuribayashi, Ryosuke Nakamura, Yoshiro Saito
Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. The Project for the Promotion of Progressive Medicine, Medical Devices, and Regenerative Medicine by the Ministry of Health, Labour and Welfare, performed by Tohoku University, reported scientific information on the evaluation of genetic polymorphisms, mainly on drug metabolizing enzymes and transporters, during non-clinical studies and phase I clinical trials in Japanese subjects/patients...
March 15, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29610054/comparison-of-protein-expression-between-human-livers-and-the-hepatic-cell-lines-hepg2-hep3b-and-huh7-using-swath-and-mrm-hr-proteomics-focusing-on-drug-metabolizing-enzymes
#7
Jian Shi, Xinwen Wang, Lingyun Lyu, Hui Jiang, Hao-Jie Zhu
Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method...
March 10, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29610053/collaborative-study-using-common-samples-to-evaluate-the-performance-of-anti-drug-antibody-assays-constructed-by-different-companies
#8
Shingo Niimi, Kazuhiro Nishimiya, Masanobu Nishidate, Tetsu Saito, Kyoko Minoura, Kenta Kadotsuji, Jin Shimakura, Hiroko Shigemizu, Jun Hosogi, Maiko Adachi, Tsutomu Hashimoto, Tamiki Mori, Hideki Harada, Ken-Ichi Yamamoto, Takahiro Nakamura, Tatsuki Nomura, Itadaki Yamaguchi, Kazuhiko Sonehara, Akiko Ishii-Watabe, Nana Kawasaki
This study was undertaken to evaluate the performance of anti-drug antibody (ADA) assays constructed by each participating company using common samples including ADA, drug and human serum. The ADA assays constructed by each company showed good sensitivity and precision for evaluation of ADA. Cut points for screening and confirmatory assays and assay selectivity were determined by various calculation methods. In evaluations of blind ADA samples, nearly similar results were obtained by the study companies in determinations of whether samples were positive or negative except at the lowest sample concentration (5 ng/mL)...
March 8, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29606543/a-phase-i-open-label-single-dose-micro-tracer-mass-balance-study-of-14-c-labeled-asp7991-in-healthy-japanese-male-subjects-using-accelerator-mass-spectrometry
#9
Daisuke Miyatake, Naoyuki Nakada, Akitsugu Takada, Kota Kato, Yuta Taniuchi, Masataka Katashima, Taiji Sawamoto
ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [14 C]ASP7991 were investigated in six healthy male subjects after a single oral dose of [14 C]ASP7991 [1 mg, 18.5 kBq (500 nCi)] in solution. [14 C] radioactivity in plasma, urine and feces was analyzed using Accelerator mass spectrometry. ASP7991 was rapidly absorbed, metabolized and excreted...
March 7, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29454704/selective-inhibition-of-cyp2c8-by-fisetin-and-its-methylated-metabolite-geraldol-in-human-liver-microsomes
#10
Riya Shrestha, Ju-Hyun Kim, Wongshik Nam, Hye Suk Lee, Jae-Mok Lee, Sangkyu Lee
Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Although the in vivo and in vitro effects of fisetin and its metabolites are frequently reported, studies on herb-drug interactions have not yet been performed. This study was designed to investigate the inhibitory effect of fisetin and geraldol on eight isoforms of human cytochrome P450 (CYP) by using cocktail assay and LC-MS/MS analysis...
April 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29402634/a-cyp2b6-humanized-mouse-model-and-its-potential-applications
#11
REVIEW
Lei Li, Qing-Yu Zhang, Xinxin Ding
CYP2B6 is a human microsomal cytochrome P450 enzyme with broad substrate selectivity. CYP2B6 is the only functional member of the human CYP2B gene subfamily, which differs from the situation in rodents, such as mouse, where multiple functional Cyp2b genes are expressed. Recent studies with Cyp2b knockout or knockdown mouse models have yielded insights into the in vivo roles of mouse CYP2B enzymes in drug disposition and xenobiotic toxicity. A CYP2B6-humanized mouse model (CYP2A13/2B6/2F1-transgenic/Cyp2abfgs-null), which expresses human CYP2B6 in the liver, and human CYP2A13 and CYP2F1 in the respiratory tract, but not any of the mouse Cyp2b genes, has also been established...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29398302/organs-on-a-chip-current-applications-and-consideration-points-for-in-vitro-adme-tox-studies
#12
REVIEW
Seiichi Ishida
Assay systems using in vitro cultured cells are increasingly applied for evaluation of the efficacy, safety, and toxicity of drug candidates. In vitro cell-based assays have two main applications in the drug discovery process: searching for a compound that is effective against the target disease (seed investigation) and confirmation of safety during use of the identified compounds (safety assessment). Currently available in vitro cell-based assays have been designed to evaluate the efficacy and toxicity in single organs, but the in vivo pharmacokinetics and pharmacodynamics of the administered drug candidates have not been considered...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29398301/human-and-mouse-artificial-chromosome-technologies-for-studies-of-pharmacokinetics-and-toxicokinetics
#13
REVIEW
Daisuke Satoh, Satoshi Abe, Kaoru Kobayashi, Yoshihiro Nakajima, Mitsuo Oshimura, Yasuhiro Kazuki
In the earliest stage of drug discovery/development, various cell-based models and animal models were used for the prediction of human pharmacokinetics and toxicokinetics. Unfortunately, drugs under development are often discontinued because their nonclinical results do not extrapolate to human clinical studies in relation to either safety or efficacy. Therefore, it is important to improve the time- and cost-effectiveness of drug development. This might be achieved by developing new technologies including pharmacokinetics and toxicokinetics models that use human and mouse artificial chromosome vectors (HACs/MACs)...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29361388/quantitative-analysis-of-elevation-of-serum-creatinine-via-renal-transporter-inhibition-by-trimethoprim-in-healthy-subjects-using-physiologically-based-pharmacokinetic-model
#14
Tomohisa Nakada, Toshiyuki Kudo, Toshiyuki Kume, Hiroyuki Kusuhara, Kiyomi Ito
Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29338933/physiological-based-pharmacokinetic-modeling-to-estimate-in-vivo-ki-of-ketoconazole-on-renal-p-gp-using-human-drug-drug-interaction-study-result-of-fesoterodine-and-ketoconazole
#15
Masayo Oishi, Yuma Takano, Yutaka Torita, Bimal Malhotra, Koji Chiba
This study was conducted to estimate in vivo inhibition constant (Ki) of ketoconazole on renal P-glycoprotein (P-gp) using human drug-drug interaction (DDI) study result of fesoterodine and ketoconazole. Fesoterodine is a prodrug which is extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is then further metabolized via Cytochrome P450 (CYP) 2D6 and CYP3A4. It is reported that 5-HMT is a substrate of P-gp whereas fesoterodine is not. Renal clearance of 5-HMT is approximately two-times greater than renal glomerular filtration rate...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29338932/functional-characteristics-of-a-renal-h-lipophilic-cation-antiport-system-in-porcine-llc-pk-1-cells-and-rats
#16
Ryutaro Matsui, Ryutaro Hattori, Youhei Usami, Masumi Koyama, Yuki Hirayama, Emi Matsuba, Yukiya Hashimoto
We have recently found an H+ /quinidine (a lipophilic cation, QND) antiport system in Madin-Darby canine kidney (MDCK) cells. The primary aim of the present study was to evaluate whether the H+ /lipophilic cation antiport system is expressed in porcine LLC-PK1 cells. That is, we investigated uptake and/or efflux of QND and another cation, bisoprolol, in LLC-PK1 cells. In addition, we studied the renal clearance of bisoprolol in rats. Uptake of QND into LLC-PK1 cells was decreased by acidification of the extracellular pH or alkalization of the intracellular pH...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29306501/state-of-the-art-technologies-in-vitro-and-in-vivo-models-mimicking-the-human-drug-metabolism-and-pharmacokinetics
#17
EDITORIAL
Kenji Tabata, Hideki Hirabayashi
No abstract text is available yet for this article.
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29241692/in-vitro-inhibitory-effects-of-major-bioactive-constituents-of-andrographis-paniculata-curcuma-longa-and-silybum-marianum-on-human-liver-microsomal-morphine-glucuronidation-a-prediction-of-potential-herb-drug-interactions-arising-from-andrographolide-curcumin
#18
Verawan Uchaipichat
This study aimed to investigate the liver microsomal inhibitory effects of silybin, silychristin, andrographolide, and curcumin by using morphine as an in vitro UGT2B7 probe substrate, and predict the magnitude of the herb-drug interaction arising from these herbal constituents' inhibition in vivo. Studies were performed in the incubation with and without bovine serum albumin (BSA). Andrographolide and curcumin showed a marked inhibition on morphine 3- and 6-glucuronidation with IC50 of 50&87 and 96&111 μM, respectively...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29233455/genetic-variation-of-cytochrome-p450-in-uyghur-chinese-population
#19
Guangzhao Qi, Duolu Li, Xiaojian Zhang
Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese...
February 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29223463/terfenadine-metabolism-of-human-cytochrome-p450-2j2-containing-genetic-variations-g312r-p351l-and-p115l
#20
Dabin Jeong, Hyoung-Goo Park, Young-Ran Lim, Yejin Lee, Vitchan Kim, Myung-A Cho, Donghak Kim
The human cytochrome P450 2J2 is involved in several metabolic reactions, including the oxidation of important therapeutics and epoxidation of endogenous arachidonic acid. At least ten genetic variations of P450 2J2 have been identified, but their effects on enzymatic activity have not been clearly characterized. Here, we evaluated the functional effects of three genetic variations of P450 2J2 (G312R, P351L, and P115L). Recombinant enzymes of wild-type and three variant P450 2J2 were heterologously expressed in Escherichia coli and purified...
February 2018: Drug Metabolism and Pharmacokinetics
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