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Drug Metabolism and Pharmacokinetics

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
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
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
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
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
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
Mihwa Kwon, Hyeon-Kyeong Ji, Soo Hyeon Goo, So Jeong Nam, Yun Ju Kang, Eunyoung Lee, Kwang Hyeon Liu, Min-Koo Choi, Im-Sook Song
We aimed to investigate the underlying mechanisms for low bioavailability of Platycodin D (PD) in rats. The bioavailability of PD was 1.89% with different half-lives depending on the administration route (2.14 ± 0.18 h for intravenous injection vs 5.42 ± 1.9 h for oral administration). The mean absorption time was 6.3 h calculated from the mean residence time of both administration routes. Consistent with these parameters, rat intestinal permeability using 3 different intestinal segments showed a low but greatest permeability in lower ileum (0...
June 8, 2017: Drug Metabolism and Pharmacokinetics
Yasuhiro Uno, Akinori Matsushita, Norie Murayama, Hiroshi Yamazaki
No abstract text is available yet for this article.
June 2017: Drug Metabolism and Pharmacokinetics
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
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
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
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
Yasushi Yamazoe, Kouichi Yoshinari
In our previous paper (Drug Metabolism Parmacokinet31: 363, 2016), a simulation system for ligand interactions of human CYP1A2 was developed using "Template" composed of hexagonal grids focusing on polyaromatic hydrocarbons (PAHs). The system has been expanded for the application of non-PAH chemicals including medical drugs, industrial chemicals and natural products in the present study. Additions of two Templates C and D around Ring C/E and Ring B, respectively, perpendicular each to Template A, offered the accommodation of non-PAH substrates...
May 29, 2017: Drug Metabolism and Pharmacokinetics
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
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
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
Mayuko Koyama, Tatsuya Shirahata, Rika Hirashima, Yoshinori Kobayashi, Tomoo Itoh, Ryoichi Fujiwara
Glycyrrhetinic acid (GA) is an active metabolite of glycyrrhizin, which is a main constituent in licorice (Glycyrrhiza glabra). While GA exhibits a wide variety of pharmacological activities in the body, it is converted to a toxic metabolite GA 3-O-glucuronide by hepatic UDP-glucuronosyltransferases (UGTs). To avoid the development of the toxic metabolite-induced pseudohyperaldosteronism (pseudoaldosteronism), there is a limitation in maximum daily dosage of licorice and in combined usage of other glycyrrhizin-containing natural medicine...
May 4, 2017: Drug Metabolism and Pharmacokinetics
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
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
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
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