Read by QxMD icon Read

Drug Metabolism and Pharmacokinetics

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...
October 13, 2016: Drug Metabolism and Pharmacokinetics
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...
September 19, 2016: Drug Metabolism and Pharmacokinetics
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)...
September 17, 2016: Drug Metabolism and Pharmacokinetics
Hang He, Ya-Li Nie, Jiang-Feng Li, Xiang-Guang Meng, Wei-Hong Yang, Yu-Long Chen, Shu-Jie Wang, Xiaochao Ma, Quan-Cheng Kan, Li-Rong Zhang
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus...
September 9, 2016: Drug Metabolism and Pharmacokinetics
Almudena Sánchez-Martín, Salvador Cabrera Figueroa, Raquel Cruz, Liliana Porras-Hurtado, Fernando Calvo-Boyero, Mahmood Rasool, Alfonso Domínguez-Gil Hurlé, Angel Carracedo
Genetic factors have a significant impact on the PK variability of EFV, much higher than other non-genetic factors, such as demography. In this work we have performed a comprehensive PG analysis of genes encoding the major metabolizing enzymes and transporters of EFV, establishing a clear relationship between the PK parameters and genetic factors, which explain 50% of the variability in EFV PK parameters. The most relevant associations for metabolizing enzymes were found in CYP2B6 (rs3745274), in agreement with previous studies...
October 2016: Drug Metabolism and Pharmacokinetics
Yasushi Yamazoe, Kazumi Ito, Yoshiya Yamamura, Ryutaro Iwama, Kouichi Yoshinari
This prediction system is based on placements of CYP1A2-substrates on a hexagonal-grid template in a way following the rule generated from the relationship of the substrate-structure and selective-area uses on the template, and also the rule for a triggering-event to initiate the catalytic reactions. Clear relationship found between the placements and preferred-order of regioselective reactions from the comparison of experimental data of polyaromatic hydrocarbon (PAH)-substrates was implemented in this system...
October 2016: Drug Metabolism and Pharmacokinetics
Michał Romański, Anna Kasprzyk, Agnieszka Karbownik, Franciszek K Główka
Treosulfan (TREO) has an established position in chemotherapy of advanced ovarian cancer but has been also applied in uveal melanoma patients. Moreover, it is used as an orphan drug for a myeloablative conditioning prior to stem cell transplantation. In this paper, biodistribution of prodrug TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into aqueous humor of the eye was studied for the first time. For that purpose, alone TREO and the mixture of TREO, S,S-EBDM and S,S-DEB were administered intravenously to New Zealand White rabbits...
October 2016: Drug Metabolism and Pharmacokinetics
Yoshiyuki Shirasaka, Nora Lee, Weibin Zha, David Wagner, Joanne Wang
Metformin is widely used for the treatment of type II diabetes mellitus. It was reported to be substrate of OCT3/Oct3, which is expressed in the brush boarder membrane of the enterocytes. However, the role of OCT3/Oct3 in the intestinal absorption process of metformin remains obscure. In the present study, we aimed to clarify the impact of Oct3 on the oral bioavailability and pharmacokinetics of metformin in mice, by means of in vivo pharmacokinetic study using wild-type (Oct3(+/+)) and Oct3-knockout (Oct3(-/-)) mice...
October 2016: Drug Metabolism and Pharmacokinetics
Masanori Nakakariya, Akihiko Goto, Nobuyuki Amano
DDI could be caused by the inhibition of OATP-mediated hepatic uptakes. The aim of this study is to set the risk criteria for the compounds that would cause DDI via OATP inhibition at the drug discovery stage. The IC50 values of OATP inhibitors for human OATP-mediated atorvastatin uptake were evaluated in the expression system. In order to set the risk criteria for OATP inhibition, the relationship was clarified between OATP inhibitory effect and severe adverse effects of OATP substrates, rhabdomyolysis, hyperbilirubinemia and jaundice...
October 2016: Drug Metabolism and Pharmacokinetics
Naoya Kameyama, Kaoru Kobayashi, Shoko Shimizu, Yuki Yamasaki, Mika Endo, Mari Hashimoto, Tomomi Furihata, Kan Chiba
Pregnane X receptor (PXR) is involved in the transactivation of ABCB1 gene by rifampicin (RIF). However, we found that increase in ABCB1 mRNA by RIF was observed in LS180 cells but not in HepG2 cells. Since both cell lines expressed PXR equally, we hypothesized that a factor(s) other than PXR is responsible for PXR-mediated transactivation of the ABCB1 gene. Reporter activities of a distal enhancer module containing direct repeat 4 (DR4) motifs were increased by RIF in LS180 cells but not in HepG2 cells. Mutation of the DR4 motifs diminished the increase in reporter activities in LS180 cells...
October 2016: Drug Metabolism and Pharmacokinetics
A Petitcollin, R Crochette, C Tron, M-C Verdier, C Boglione-Kerrien, C Vigneau, E Bellissant, F Lemaitre
Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension...
October 2016: Drug Metabolism and Pharmacokinetics
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...
September 2, 2016: Drug Metabolism and Pharmacokinetics
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...
August 31, 2016: Drug Metabolism and Pharmacokinetics
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)...
August 18, 2016: Drug Metabolism and Pharmacokinetics
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...
August 18, 2016: Drug Metabolism and Pharmacokinetics
Kazuo Umemura, Yasuhiko Ikeda, Kazunao Kondo
This randomized double-blind and placebo-controlled study assessed the pharmacodynamics and pharmacokinetics of prasugrel in healthy adult Japanese male subjects after single (n = 50) and multiple (n = 40) oral administration. With a single administration of prasugrel (2-30 mg), the plasma concentration of the active metabolite increased rapidly, reached a maximum at 30 min after administration, and then decreased rapidly within 4 h. The 5 mg and higher doses prevented ADP-induced platelet aggregation in a dose-dependent manner...
August 2016: Drug Metabolism and Pharmacokinetics
Rui Gao, Mingyi Liu, Yu Chen, Chunhua Xia, Hong Zhang, Yuqing Xiong, Shibo Huang
This study aims to characterize the glucuronidation kinetics of ursolic acid (UA) in human liver microsomes (HLMs) and intestinal microsomes (HIMs) and identify the main UDP-glucuronosyltransferases (UGTs) involved. In our present study, only one type of UA glucuronide was observed after incubation with HLMs and HIMs respectively and was identified as a UA hydroxyl O-glucuronide. The glucuronidation of UA can be shown in HLMs and HIMs with Km values of 3.29 ± 0.16 and 3.74 ± 0.22 μM and Vmax values of 0...
August 2016: Drug Metabolism and Pharmacokinetics
Akitsugu Takada, Masataka Katashima, Atsunori Kaibara, Koji Chono, Kiyomitsu Katsumata, Taiji Sawamoto, Hiroshi Suzuki, Yoshitaka Yano
Amenamevir is a novel drug that targets the viral helicase-primase complex. While dose-dependent efficacy had been observed in non-clinical studies, no clear dose dependence has been observed in humans. We therefore developed a pharmacokinetic/pharmacodynamic (PK/PD) model to explain this inconsistency between species and to clarify the immune-related healing of amenamevir in humans. The model consisted of a non-linear kinetic model for a virtual number of virus plaques as a built-in biomarker. Lesion score was defined as an endpoint of antiviral efficacy, and logit model analysis was applied to the ordered-categorical lesion score...
August 2016: Drug Metabolism and Pharmacokinetics
Xiaolin Sun, Junxiu Li, Chaorui Guo, Han Xing, Jie Xu, Yanli Wen, Zhixia Qiu, Qiuyang Zhang, Yi Zheng, Xijing Chen, Di Zhao
Curcumin can synergistically enhance docetaxel's in vitro and in vivo antitumor activity and has been co-administrated with docetaxel in clinical trials. The aim of our study is to investigate the effect of curcumin on the pharmacokinetics of docetaxel and explore its mechanism on OATP1B1, OATP1B3 and human liver microsomes (HLMs). In rats, curcumin increased the docetaxel area under the plasma concentration-time curve (AUC0-8h) and the terminal half-life (t1/2) to 1.86- and 1.55-fold, respectively. Moreover, curcumin decreased the clearance (CL) of docetaxel to 52...
August 2016: Drug Metabolism and Pharmacokinetics
Qiushi Xie, Yang Chen, Fei Liu, Zeyu Zhong, Kaijing Zhao, Zhaoli Ling, Fan Wang, Xiange Tang, Zhongjian Wang, Li Liu, Xiaodong Liu
Deoxypodophyllotoxin (DPT) is a natural lignan product which has drawn much attention due to its pharmacological properties including antitumor effect. The purpose of this study was to investigate interspecies differences in metabolism of DPT in hepatic microsomes from human (HLM), cynomolgus monkey (CyLM), rat (RLM), mouse (MLM) and dog (DLM). Incubation of DPT with hepatic microsomes from five species in the presence of NADPH resulted in formation of seven metabolites, five of which were compared with the synthetic standards...
August 2016: Drug Metabolism and Pharmacokinetics
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"