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Drug Metabolism and Pharmacokinetics

Noriko Iwamoto, Takashi Shimada
In recent studies, the development of bioanalysis technologies using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has attracted attention. Our developed nano-surface and molecular-orientation limited (nSMOL) proteolysis enables Fab-specific proteolysis and is optimal for LC-MS/MS analysis of antibody drugs and Fc-fusion proteins in biological samples. In this nSMOL method, antibodies and Fc-fusion proteins are held in pores of the particle and the subsequent proteolysis is carried out with protease-immobilized nanoparticles...
October 19, 2018: Drug Metabolism and Pharmacokinetics
Shawn A Means, Harvey Ho
The metabolism zonation in liver lobules is well known yet its incorporation into the mathematical models of acetaminophen (APAP) metabolism is still primitive - only the oxidation pathway via reaction with the cytochrome P450 (CYP450) has been considered, yet the zonal heterogeneity exhibits in all three pathways including sulphation, glucuronidation and oxidation. In this paper we present a novel computational method where an intracellular APAP metabolism model is integrated into a Finite Element Model (FEM) of sinusoids, and the zonal heterogeneity in three metabolism pathways are all incorporated...
October 8, 2018: Drug Metabolism and Pharmacokinetics
Lisa K Stamp, Mary Wallace, Rebecca L Roberts, Christopher Frampton, Jeffrey N Miner, Tony R Merriman, Nicola Dalbeth
No abstract text is available yet for this article.
September 18, 2018: Drug Metabolism and Pharmacokinetics
Yasuhiro Uno, Makiko Shimizu, Hiromi Yoda, Yumi Origuchi, Hiroshi Yamazaki
Polymorphic human flavin-containing monooxygenase (FMO) 3 is an important drug-metabolizing enzyme for nitrogen- or sulfur-containing compounds. Cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, have corresponding FMO3 molecular and enzymatic similarities to humans; however, genetic polymorphisms have not been investigated in macaques. In this study, re-sequencing of FMO3 in 64 cynomolgus and 32 rhesus macaques found a total of 18 non-synonymous variants. Nine variants were unique to cynomolgus macaques, of which 4 (including Q506K) were found only in Indochinese, 4 (including V299I, E348H, and G530A) only in Indonesian lineages, and one was common...
September 7, 2018: Drug Metabolism and Pharmacokinetics
Keiko Hikino, Koya Fukunaga, Taisei Mushiroda
In this study, we aimed to understand the gap in coverage of pharmacogenomic (PGx) biomarkers between Japan and the US. PGx biomarkers (1) in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines; (2) that are CPIC level A or B; or (3) have US Food and Drug Administration (FDA)-approved drug labels, were determined. Subsequently, their coverage by US health insurance companies and the National Health Insurance (NHI) in Japan was investigated. We identified the top six health insurance companies with the largest market shares in the US and investigated the coverage for the PGx biomarkers by these health insurers, Medicare, Medicaid, and the NHI in Japan...
September 1, 2018: Drug Metabolism and Pharmacokinetics
Ayuko Imaoka, Kohei Seki, Takeshi Akiyoshi, Hisakazu Ohtani
Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25 g of activated charcoal under a fasted condition, but not affected by 2 g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. The aim of this study was to quantitatively evaluate the effect of food intake on drug interactions caused by adsorption to activated charcoal in the gastrointestinal tract in rats...
August 28, 2018: Drug Metabolism and Pharmacokinetics
Takahiro Saito, Evelyn Marie Gutiérrez Rico, Aoi Kikuchi, Akira Kaneko, Masaki Kumondai, Fumika Akai, Daisuke Saigusa, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka
Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolic activation of primaquine, an antimalarial drug. CYP2D6 is genetically polymorphic, and these polymorphisms are associated with interindividual variations observed in the therapeutic efficacy of primaquine. To further understand this association, we performed in vitro enzymatic analyses of the wild-type CYP2D6.1 and 49 CYP2D6 allelic variants, which were expressed in 293FT cells, using primaquine as a substrate. The concentrations of CYP2D6 variant holoenzymes were measured by using carbon monoxide (CO)-reduced difference spectroscopy, and the wild type and 27 variants showed a peak at 450 nm...
August 25, 2018: Drug Metabolism and Pharmacokinetics
Masaki Kumondai, Akio Ito, Eiji Hishinuma, Aoi Kikuchi, Takahiro Saito, Masamitsu Takahashi, Chiharu Tsukada, Sakae Saito, Jun Yasuda, Masao Nagasaki, Naoko Minegishi, Masayuki Yamamoto, Akira Kaneko, Isao Teramoto, Masatsugu Kimura, Noriyasu Hirasawa, Masahiro Hiratsuka
Genetic polymorphisms contribute to inter-individual variability in the metabolism of multiple clinical drugs, including warfarin, thiopurines, primaquine, and aminoglycosides. A rapid and sensitive clinical assessment of various genome biomarkers is, therefore, required to predict the individual responsiveness of each patient to these drugs. In this study, we developed a novel genotyping method for the detection of nine pharmacogene variants that are important in the prediction of drug efficiency and toxicity...
August 22, 2018: Drug Metabolism and Pharmacokinetics
Keisuke Oda, Nobuhiro Mori, Masayoshi Okumi, Miyuki Furusawa, Masashi Ishiguro, Kazuyuki Inoue, Satoshi Shuto, Kohei Unagami, Hideki Ishida, Kazunari Tanabe, Teruo Murakami
The cellular uptake of mizoribine (MZR), an immunosuppressant, and metabolism of MZR to MZR-5'- monophosphate (MZRP), an active metabolite, were evaluated in L5178Y-R mouse lymphoma cells and peripheral blood mononuclear cells (PBMCs) of rats and kidney transplant recipients (KTRs, n = 22). Real-time PCR analysis revealed the expression of ENT1 and ENT2 mRNAs, but not of CNTs, in L5178Y-R cells and rat's PBMCs. In L5178Y-R cells, the uptake of MZR was suppressed by adenosine, a substrate for ENT1 and ENT2, but not by 5-(4-nitrobenzyl)-6-thioinosine (0...
October 2018: Drug Metabolism and Pharmacokinetics
Y Amy Siu, Ming-Hong Hao, Vaishali Dixit, W George Lai
Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km , Ki , and Vmax of 67.2 μM, 12.6 μM, and 1.33 μM/min, respectively. In human liver microsomes (HLMs), a concentration-dependent inhibition of celecoxib hydroxylation by quinidine was observed after CYP2C9 and CYP3A4 were inhibited. In individual HLMs with variable CYP2D6 activities, a significant correlation was observed between celecoxib hydroxylation and CYP2D6-selective dextromethorphan O-demethylation when CYP2C9 and CYP3A4 activities were suppressed (r = 0...
October 2018: Drug Metabolism and Pharmacokinetics
Yaling Dou, Pan Peng, Congli Cai, Ali Ye, Lingjun Kong, Rui Zhang
HLA-B*58:01 has been demonstrated to be associated with allopurinol-induced severe cutaneous adverse reactions. Since HLA-B*58:01 is too complicated to be identified, it is necessary to select an appropriate surrogate biomarker. In Japan, the rs9263726 allele was considered as a surrogate biomarker for HLA-B*58:01, but this was not the case with the Australian cohort. Due to the conflict results, in this study, we aim to demonstrate whether the rs9263726 allele is a surrogate biomarker for HLA-B*58:01 in Han Chinese population...
October 2018: Drug Metabolism and Pharmacokinetics
Yuki Kimura, Masaki Kobayashi, Masaru Asari, Issei Higuchi, Katsuya Narumi, Ayako Furugen, Ken Iseki
MCT1 (SLC16A1), MCT4 (SLC16A3), and MCT11 (SLC16A11) are members of the monocarboxylate transporter (MCT) family. MCT1 and MCT4 transport pH-related monocarboxylates, such as lactate and pyruvate. MCT11 may also be a proton-coupled monocarboxylate transporter. Although alterations of these substrates are involved in the pathology of cancer and diabetes, little is known about MCT polymorphisms. In this study, genetic variation was evaluated in SLC16A1, SLC16A3, and SLC16A11 in the Japanese population (healthy volunteers, n = 92)...
October 2018: Drug Metabolism and Pharmacokinetics
Yoko Tamaki, Kunio Maema, Makoto Kakara, Masato Fukae, Ryoko Kinoshita, Yushi Kashihara, Shota Muraki, Takeshi Hirota, Ichiro Ieiri
The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7...
August 16, 2018: Drug Metabolism and Pharmacokinetics
Naoyuki Tatsumi, Shinsaku Tokumitsu, Masataka Nakano, Tatsuki Fukami, Miki Nakajima
UDP-Glucuronosyltransferase (UGT) 1A enzymes catalyze the glucuronidation of various compounds. Since no correlation was observed between the protein and mRNA expression of some UGT1A isoforms in the human liver, the involvement of post-transcriptional regulation was hypothesized. We examined whether microRNAs (miRNAs) regulate human UGT1A, focusing on the predicted miR-141-3p. A luciferase assay revealed that a miRNA recognition element for miR-141-3p in the 3'-untranslated region of UGT1A mRNA was functional...
August 2018: Drug Metabolism and Pharmacokinetics
Misato Nakamura, Hidetaka Yamanaka, Ami Oguro, Susumu Imaoka
Bisphenol A (BPA) is an endocrine-disrupting chemical, and activates the aryl hydrocarbon receptor (AhR) and the estrogen receptor, leading to the induction of drug metabolizing enzymes. In this study, we found that BPA increased nitric oxide (NO) levels but not reactive oxygen species (ROS) levels in the human hepatoma cell line, Hep3B, and induced drug-metabolizing enzymes such as UDP-glucuronosyltransferase (UGT). Nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported to be activated by ROS through inactivation of its regulating protein, Kelch-like ECH-associated protein (Keap1), and to be the key mediator of phase I and phase II drug metabolizing enzymes, and phase III drug transporters...
August 2018: Drug Metabolism and Pharmacokinetics
Jun Terashima, Yoko Jimma, Keiko Jimma, Shuko Hakata, Maako Yachi, Wataru Habano, Shogo Ozawa
Most of cytochrome P450 (CYP) expressions are regulated by nuclear receptors. The regulation pathways of transcription are activated by binding of the ligand to the receptor. Many combination of CYPs and nuclear receptors in transcriptional regulation have been reported. However, we have reported that the combination changes depending on culture condition on the same type of cells. The regulation pathway of CYP1A expression is different between 2D monolayer cultured cells and 3D spheroids of human liver cancer cells...
August 2018: Drug Metabolism and Pharmacokinetics
Christina Y S Chan, Owain Roberts, Rajith K R Rajoli, Neill J Liptrott, Marco Siccardi, Lisa Almond, Andrew Owen
The first-order degradation rate constant (kdeg ) of cytochrome P450 (CYP) enzymes is a known source of uncertainty in the prediction of time-dependent drug-drug interactions (DDIs) in physiologically-based pharmacokinetic (PBPK) modelling. This study aimed to measure CYP kdeg using siRNA to suppress CYP expression in primary human hepatocytes followed by incubation over a time-course and tracking of protein expression and activity to observe degradation. The magnitude of gene knockdown was determined by qPCR and activity was measured by probe substrate metabolite formation and CYP2B6-Glo™ assay...
August 2018: Drug Metabolism and Pharmacokinetics
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)...
August 2018: Drug Metabolism and Pharmacokinetics
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...
June 2018: Drug Metabolism and Pharmacokinetics
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...
June 2018: Drug Metabolism and Pharmacokinetics
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