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Drug Metabolism and Pharmacokinetics

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https://www.readbyqxmd.com/read/28522025/corrigendum-to-genetic-polymorphism-of-cynomolgus-and-rhesus-macaque-cyp2c9-drug-metab-pharmacokinet-30-2015-130-132
#1
Yasuhiro Uno, Akinori Matsushita, Norie Murayama, Hiroshi Yamazaki
No abstract text is available yet for this article.
April 25, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28318879/evidences-for-salbutamol-metabolism-by-respiratory-and-liver-cell-lines
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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/28412023/precise-prediction-of-activators-for-the-human-constitutive-androstane-receptor-using-structure-based-three-dimensional-quantitative-structure-activity-relationship-methods
#8
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...
February 9, 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
#9
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/28017537/human-leukocyte-antigen-and-idiosyncratic-adverse-drug-reactions
#10
REVIEW
Toru Usui, Dean J Naisbitt
A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis...
February 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28129974/prediction-of-the-potential-risk-of-idiosyncratic-drug-toxicity
#11
EDITORIAL
Kousei Ito, Kaoru Kobayashi
No abstract text is available yet for this article.
December 21, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28111103/potentiation-of-the-anticoagulation-effect-of-warfarin-by-the-herbal-remedy-shu-jing-hwo-shiee-tang-in-rats-the-dosing-regimen-and-pharmacokinetic-interaction
#12
Yune-Fang Ueng, Chung-Kuang Lu, Sien-Hung Yang, Hong-Jaan Wang, Chiung-Chiao Huang
The herbal remedy Shu-Jing-Hwo-Shiee-Tang (SJHST) has been used in traditional Chinese medical care for the treatment of osteoarthritis. This study aims to examine the influence of SJHST on the oxidation and anticoagulation effect of warfarin in male rats. In three SJHST preparations (S1-S3), hesperidin, gentiopicrin, and paeoniflorin were identified as chemical marker ingredients. The inhibition of liver microsomal warfarin 7-hydroxylation (WOH) activity by 50% methanolic extracts of SJHST was potentiated by β-glucosidase pretreatment, but not by NADPH-fortified microsomal preincubation...
December 8, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28340950/pharmacokinetics-and-bioavailability-of-oral-single-dose-maleic-acid-in-biofluids-of-sprague-dawley-rats
#13
Charlene Wu, Hsin-Chang Chen, Yu-Syuan Luo, Su-Yin Chiang, Kuen-Yuh Wu
Maleic acid (MA) was purposefully adulterated in an array of starch-based foods in Taiwan, inciting a food safety incident. Due to limited data on the pharmacokinetics and bioavailability of ingested MA, we studied pharmacokinetic (PK) parameters in serum and urine of Sprague Dawley rats. Three groups of male and female rats were given three doses of MA by oral gavage; biofluid samples were collected accordingly. Data demonstrated that a non-compartment model best described MA's linear kinetic behavior upon ingestion...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27876352/quantitative-analysis-of-pharmacokinetic-profiles-of-verapamil-and-drug-drug-interactions-induced-by-a-cyp-inhibitor-using-a-stable-isotope-labeled-compound
#14
Makoto Kataoka, Chie Kojima, Kazuki Ueda, Keiko Minami, Haruki Higashino, Shinji Sakuma, Kazutaka Togashi, Kuninori Mutaguchi, Shinji Yamashita
The purpose of the present study is to demonstrate a useful approach (isotope-IV method) for analyzing drug-drug interactions (DDIs) following the oral administration of drugs using stable isotope-labeled compounds. Verapamil hydrochloride (VER) was used as a drug model. Deuterium-labeled VER (VER-d6, 0.005 mg/kg) was intravenously administered to rats with or without a pre-treatment with 1-aminobenzotriazole (ABT, 100 mg/kg), a potent CYP inhibitor, 1.5 h after the oral administration of VER (1 mg/kg)...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27839692/a-possible-role-for-hla-drb1-04-06-in-statin-related-myopathy-in-japanese-patients
#15
Kimie Sai, Kouji Kajinami, Hironobu Akao, Mizuho Iwadare, Ryoko Sato-Ishida, Yasuyuki Kawai, Kenji Takeda, Takashi Tanimoto, Takashi Yamano, Takashi Akasaka, Tatsuro Ishida, Ken-Ichi Hirata, Keijiro Saku, Shusuke Yagi, Takeshi Soeki, Masataka Sata, Masafumi Ueno, Shunichi Miyazaki, Aya Shiraki, Jun-Ichi Oyama, Koichi Node, Koichi Sugamura, Hisao Ogawa, Kouichi Kurose, Keiko Maekawa, Yumiko Matsuzawa, Takuya Imatoh, Ryuichi Hasegawa, Yoshiro Saito
Statin-related myopathy (SRM) is a clinically important adverse reaction. Recent pharmacogenetic research, mainly in non-Asian populations, have indicated clinical relevance of some of genetic biomarkers to SRM, but predictive markers for SRM in Asian populations including Japanese has not yet been established. This study was aimed to identify clinically important genetic markers associated with SRM in Japanese patients. Allele frequencies of the three reported candidate markers - SLCO1B1 rs4149056, RYR2 rs2819742, and GATM rs9806699 - and carrier frequencies of HLA types were compared between patients with SRM patients (n = 52) and healthy Japanese subjects (n = 2878 or 86 (for rs9806699) as controls)...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27839691/modeling-of-aceclofenac-metabolism-to-major-metabolites-in-healthy-volunteers
#16
Eunyoung Kim, Chunhwa Ihm, Wonku Kang
Aceclofenac has been used widely as a potent analgesic and anti-inflammatory drug. Aceclofenac is converted to 4'-hydroxyaceclofenac and diclofenac via CYP2C9-mediated hydroxylation and hydrolysis, respectively. CYP2C9 also mediates the hydroxylation of diclofenac to yield 4'-hydroxydiclofenac and the hydrolysis of 4'-hydroxyaceclofenac to 4'-hydroxydiclofenac. We aimed to model the metabolism of aceclofenac in volunteers using a compartmental modeling approach. After an oral dose of 100 mg aceclofenac in volunteers, plasma concentrations of aceclofenac and its three metabolites were measured...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27836712/application-of-substrate-depletion-assay-to-evaluation-of-cyp-isoforms-responsible-for-stereoselective-metabolism-of-carvedilol
#17
Masahiro Iwaki, Toshiro Niwa, Saya Bandoh, Megumi Itoh, Hitomi Hirose, Atsushi Kawase, Hiroshi Komura
To evaluate the relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation, enantioselective metabolism of CAR was investigated in human liver microsomes (HLMs) and recombinant human CYPs by using the substrate depletion assay. CYP2D6 exhibited the highest contribution to the metabolism of R-CAR, followed by CYP3A4, CYP1A2, and CYP2C9, whereas the metabolism of the S-enantiomer was mainly mediated by CYP1A2, followed by CYP2D6 and CYP3A4. In HLMs, metabolism of R- and S-CAR was markedly inhibited by quinidine; R-CAR metabolism (57-61% decrease) was more inhibited than S-CAR metabolism (37-43% decrease), and furafylline and ketoconazole almost equally inhibited metabolism of both enantiomers by 25-32% and 30-50%, respectively...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27836711/effect-of-cigarette-smoke-extract-on-p-glycoprotein-function-in-primary-cultured-and-newly-developed-alveolar-epithelial-cells
#18
Mikihisa Takano, Ryosuke Naka, Yoshihiro Sasaki, Saori Nishimoto, Ryoko Yumoto
The effect of cigarette smoke extract (CSE) on P-glycoprotein (P-gp) function in the distal lung is unclear. In this study, we first examined the expression and function of P-gp and the effect of CSE in rat primary cultured alveolar epithelial cells. The expression of P-gp protein was observed in type I-like cells, but not in type II cells. In type I-like cells, rhodamine 123 (Rho123) accumulation was enhanced by various P-gp inhibitors such as verapamil and cyclosporine A. In addition, the expression of P-gp mRNAs, mdr1a and mdr1b, as well as P-gp activity increased along with the transdifferentiation...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27829538/pharmacokinetic-drug-interaction-study-between-overactive-bladder-drugs-mirabegron-and-tolterodine-in-japanese-healthy-postmenopausal-females
#19
Yuki Nomura, Hiromi Iitsuka, Junko Toyoshima, Kentaro Kuroishi, Toshifumi Hatta, Atsunori Kaibara, Masataka Katashima, Selina Moy, Taiji Sawamoto
Mirabegron, the first selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1-7 and co-administered with mirabegron 50 mg from Days 8-14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27793475/biochemical-analysis-of-recombinant-cyp4a11-allelic-variant-enzymes-w126r-k276t-and-s353g
#20
Songhee Han, Gun-Su Cha, Young-Jin Chun, Chang Hoon Lee, Donghak Kim, Chul-Ho Yun
Human CYP4A11 is the major ω-hydroxylase of fatty acids in the liver and kidneys. It produces 20-hydroxyeicosatetraenoic acid as well as hydroxylates fatty acids. In this study, we investigated the biochemical properties of three alleles of CYP4A11: W126R, K276T, and S353G. Site-directed mutagenesis of the wild type CYP4A11 was performed, to construct the W126R, K276T, and S353G variant clones. The CYP4A11 wild type and variant constructs were heterologously expressed in Escherichia coli. CO-binding spectra showed the expression of the wild type, K276T and S353G variants, indicating the functional P450 holoenzyme...
December 2016: Drug Metabolism and Pharmacokinetics
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