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Drug Metabolism and Pharmacokinetics

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https://www.readbyqxmd.com/read/29306501/state-of-the-art-technologies-in%C3%A2-vitro-and-in%C3%A2-vivo-models-mimicking-the-human-drug-metabolism-and-pharmacokinetics
#1
EDITORIAL
Kenji Tabata, Hideki Hirabayashi
No abstract text is available yet for this article.
December 21, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29338932/functional-characteristics-of-a-renal-h-lipophilic-cation-antiport-system-in-porcine-llc-pk1-cells-and-rats
#2
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...
December 5, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29217459/technical-aspects-of-microphysiological-systems-mps-as-a-promising-wet-human-in-vivo-simulator
#3
REVIEW
Toshiyuki Kanamori, Shinji Sugiura, Yasuyuki Sakai
Microphysiological systems (MPS) are currently attracting a lot of interest from pharmaceutical companies worldwide. In the United States and European Union, several large government projects related to MPS have been initiated, and, in Japan, pharmaceutical companies interested in MPS are watching the recent trends and developments in the field. In July 2017, the Japan Agency for Medical Research and Development initiated a research program to develop chip-based MPS. In this review, we examine the technical aspects of commercializing chip-based MPS...
November 23, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29342419/investigation-of-the-transport-of-xanthine-dehydrogenase-inhibitors-by-the-urate-transporter-abcg2
#4
Makiko Nakamura, Kyoko Fujita, Yu Toyoda, Tappei Takada, Hiroshi Hasegawa, Kimiyoshi Ichida
Hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout. A recent genome wide association study suggested that allopurinol, a serum uric acid-lowering drug that inhibits xanthine dehydrogenase, is a potent substrate of ABCG2...
November 22, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29342418/functional-characterization-of-9-cyp2a13-allelic-variants-by-assessment-of-nicotine-c-oxidation-and-coumarin-7-hydroxylation
#5
Masaki Kumondai, Hiroki Hosono, Masamitsu Maekawa, Hiroaki Yamaguchi, Nariyasu Mano, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka
Cytochrome P450 2A13 (CYP2A13) is responsible for the metabolism of chemical compounds such as nicotine, coumarin, and tobacco-specific nitrosamine. Several of these compounds have been recognized as procarcinogens activated by CYP2A13. We recently showed that CYP2A13*2 contributes to inter-individual variations observed in bladder cancer susceptibility because CYP2A13*2 might cause a decrease in enzymatic activity. Other CYP2A13 allelic variants may also affect cancer susceptibility. In this study, we performed an in vitro analysis of the wild-type enzyme (CYP2A13...
November 22, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29241692/in%C3%A2-vitro-inhibitory-effects-of-major-bioactive-constituents-of-andrographis-paniculata-curcuma-longa-and-silybum-marianum-on-human-liver-microsomal-morphine-glucuronidation-a-prediction-of%C3%A2-potential-herb-drug-interactions-arising-from-andrographolide-curcumin
#6
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...
November 20, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29338933/physiological-based-pharmacokinetic-modeling-to-estimate-in%C3%A2-vivo-ki-of-ketoconazole-on-renal-p-gp-using-human-drug-drug-interaction-study-result-of-fesoterodine-and-ketoconazole
#7
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...
November 15, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29175062/organ-body-on-a-chip-based-on-microfluidic-technology-for-drug-discovery
#8
REVIEW
Hiroshi Kimura, Yasuyuki Sakai, Teruo Fujii
Although animal experiments are indispensable for preclinical screening in the drug discovery process, various issues such as ethical considerations and species differences remain. To solve these issues, cell-based assays using human-derived cells have been actively pursued. However, it remains difficult to accurately predict drug efficacy, toxicity, and organs interactions, because cultivated cells often do not retain their original organ functions and morphologies in conventional in vitro cell culture systems...
November 13, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29223463/terfenadine-metabolism-of-human-cytochrome-p450-2j2-containing-genetic-variations-g312r-p351l-and-p115l
#9
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...
November 11, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29183653/chimeric-mice-with-humanized-liver-application-in-drug-metabolism-and-pharmacokinetics-studies-for-drug-discovery
#10
REVIEW
Yoichi Naritomi, Seigo Sanoh, Shigeru Ohta
Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism...
November 9, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29162466/specific-inhibitory-effects-of-myricetin-on-human-proton-coupled-folate-transporter-comparison-with-its-effects-on-rat-proton-coupled-folate-transporter-and-human-riboflavin-transporter-3
#11
Takahiro Yamashiro, Tomoya Yasujima, Kinya Ohta, Katsuhisa Inoue, Hiroaki Yuasa
Myricetin is a flavonoid that inhibits human proton-coupled folate transporter (hPCFT) in a transient manner, in which inhibition is manifested in its presence, and also in a sustained manner, in which inhibition induced in its presence persists after its removal. In an effort to elucidate the mechanisms involved in those, we examined if myricetin might or might not act similarly on some other transporters. Transporters examined for that, in comparison with hPCFT, were its rat ortholog (rPCFT) and human riboflavin transporter 3 (hRFVT3)...
October 31, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29174536/monophosphorylation-by-deoxycytidine-kinase-affects-apparent-cellular-uptake-of-decitabine-in-hct116-colon-cancer-cells
#12
Kumiko Ueda, Ayasa Masuda, Misaki Fukuda, Shota Tanaka, Mika Hosokawa, Seigo Iwakawa
Decitabine (DAC), a nucleoside-related DNA methylation inhibitor, is taken up into cancer cells via equilibrative nucleoside transporter 1 (ENT1), and is then monophosphorylated by deoxycytidine kinase (dCK). In the present study, we examined the contribution of dCK to the uptake of DAC in HCT116 colon cancer cells. Irinotecan and etoposide inhibited the uptake of [3H]-uridine and [3H]-DAC at 10 s and 5 min, while cytarabine and gemcitabine only inhibited that of [3H]-DAC at 5 min. Irinotecan and etoposide inhibited [3H]-DAC uptake in negative control small interfering RNA (siRNA)- or dCK siRNA-transfected cells at 10 s, whereas cytarabine and gemcitabine did not...
October 10, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29079228/species-differences-in-drug-glucuronidation-humanized-udp-glucuronosyltransferase-1-mice-and-their-application-for-predicting-drug-glucuronidation-and-drug-induced-toxicity-in-humans
#13
REVIEW
Ryoichi Fujiwara, Emiko Yoda, Robert H Tukey
More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic...
October 7, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29158009/effect-of-carbamazepine-on-expression-of-udp-glucuronosyltransferase-1a6-and-1a7-in-rat-brain
#14
Yuki Asai, Yukiko Sakakibara, Masayuki Nadai, Miki Katoh
Because UDP-glucuronosyltransferase (Ugt) 1a6 and Ugt1a7 are highly expressed in the rat brain, changes in Ugt1a6 and Ugt1a7 expression may affect the pharmacokinetics of drugs and endogenous compounds in the brain. The present study aimed to elucidate the effect of carbamazepine (CBZ), a typical UGT inducer, on Ugt1a6 and Ugt1a7 expression in the rat brain. Sprague-Dawley rats were treated intraperitoneally for 7 d with CBZ (100 mg/kg/d). Ugt1a6 and Ugt1a7 mRNAs were induced by CBZ in the cerebellum, piriform cortex, and hippocampus (Ugt1a6: 3...
October 5, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28923421/avoidance-of-food-effect-on-oral-absorption-profile-of-itraconazole-by-self-micellizing-solid-dispersion-approach
#15
Yoshiki Kojo, Kanako Kobayashi, Saori Matsunaga, Hiroki Suzuki, Yoshiki Seto, Hideyuki Sato, Satomi Onoue
The present study was aimed to avoid pharmacokinetic transitions of itraconazole (ITZ) evoked by high-fat meal intake by employing a self-micellizing solid dispersion (SMSD) approach. The dissolution behavior of SMSD/ITZ was assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). To evaluate the food effect on the oral absorption profile of ITZ, a pharmacokinetic study was conducted on orally-dosed ITZ samples in fasted and high-fat meal-fed rats. Crystalline ITZ showed a 9.0-fold higher dissolution amount of ITZ in fed-state SGF (FeSSGF) than in fasted-state SGF (FaSSGF), whereas there was no significant difference in the dissolution amount of ITZ in SMSD/ITZ between FeSSGF and FaSSGF...
October 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29137842/comparison-of-pharmacokinetics-of-newly-discovered-aromatase-inhibitors-by-a-cassette-microdosing-approach-in-healthy-japanese-subjects
#16
Hiroyuki Kusuhara, Tadayuki Takashima, Hisako Fujii, Tsutomu Takashima, Masaaki Tanaka, Akira Ishii, Shusaku Tazawa, Kazuhiro Takahashi, Kayo Takahashi, Hidekichi Tokai, Tsuneo Yano, Makoto Kataoka, Akihiro Inano, Suguru Yoshida, Takamitsu Hosoya, Yuichi Sugiyama, Shinji Yamashita, Taisuke Hojo, Yasuyoshi Watanabe
The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16...
September 21, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29174535/prediction-of-inter-individual-variability-on-the-pharmacokinetics-of-cyp2c8-substrates-in-human
#17
Kenta Haraya, Motohiro Kato, Koji Chiba, Yuichi Sugiyama
Inter-individual variability in pharmacokinetics can lead to unexpected side effects and treatment failure, and is therefore an important factor in drug development. CYP2C8 is a major drug-metabolizing enzyme known to be involved in the metabolism of over 100 drugs. In this study, we predicted the inter-individual variability in AUC/Dose of CYP2C8 substrates in healthy volunteers using the Monte Carlo simulation. Inter-individual variability in the hepatic intrinsic clearance of CYP2C8 substrates (CLint,h,2C8) was estimated from the inter-individual variability in pharmacokinetics of pioglitazone, which is a major CYP2C8 substrate...
September 15, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28942083/intracellular-localization-of-pregnane-x-receptor-in-hepg2-cells-cultured-by-the-hanging-drop-method
#18
Kosuke Yokobori, Kaoru Kobayashi, Ikuko Azuma, Hidetaka Akita, Kan Chiba
Pregnane X receptor (PXR) is localized in the cytoplasm of liver cells, whereas it is localized in the nucleus of monolayer-cultured HepG2 cells. Since cultured cells are affected by the microenvironment in which they are grown, we studied the effect of three-dimensional (3D) culture on the localization of PXR in HepG2 cells using the hanging drop method. The results showed that PXR was retained in the cytoplasm of HepG2 cells and other human hepatocarcinoma cell lines (FLC5, FLC7 and Huh7) when they were cultured by the hanging drop method...
August 26, 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
#19
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...
August 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28751116/monoamine-oxidase-b-oxidizes-a-novel-multikinase-inhibitor-kw-2449-to-its-iminium-ion-and-aldehyde-oxidase-further-converts-it-to-the-oxo-piperazine-form-in-human
#20
Jun Hosogi, Rui Ohashi, Hiroshi Maeda, Satoshi Tashiro, Eiichi Fuse, Yorihiro Yamamoto, Takashi Kuwabara
(E)-1-{4-[2-(1H-Indazol-3-yl)vinyl]benzoyl}piperazine (KW-2449) is a novel multikinase inhibitor. During our clinical study, we found that KW-2449 is mainly metabolized to its oxo-piperazine form (M1). An inhibition study suggested that monoamine oxidase-B (MAO-B) oxidizes KW-2449 to an iminium (intermediate) and aldehyde oxidase (AO) then metabolizes the intermediate to M1. The conversion of KW-2449 to the iminium (intermediate) by MAO-B was confirmed by the formation of its cyanide adduct. This cooperative metabolic pathway by MAO-B and AO was newly identified in the metabolism of piperazine...
June 22, 2017: Drug Metabolism and Pharmacokinetics
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