Hosogi, Jun Ohashi, Rui Maeda, Hiroshi Tashiro, Satoshi Fuse, Eiichi Yamamoto, Yorihiro Kuwabara, Takashi
Published in
Drug metabolism and pharmacokinetics
(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 metaboli...
Kato, Harutoshi Yamaotsu, Noriyuki Iwazaki, Norihiko Okamura, Shigeaki Kume, Toshiyuki Hirono, Shuichi
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Drug metabolism and pharmacokinetics
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 ide...
Takayama, Kazuo Mizuguchi, Hiroyuki
Published in
Drug metabolism and pharmacokinetics
Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes ...
Usui, Toru Naisbitt, Dean J
Published in
Drug metabolism and pharmacokinetics
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)/to...
Iwamura, Atsushi Nakajima, Miki Oda, Shingo Yokoi, Tsuyoshi
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Drug metabolism and pharmacokinetics
Idiosyncratic drug toxicity (IDT) is a serious problem in drug development. Reactive metabolites are postulated to be one of the causes for IDT. Conjugated metabolites are generally non-reactive except for acyl glucuronides (AGs), which are sufficiently reactive to covalently bind to endogenous proteins. Thus, it has been suggested that AGs would c...
Kanamitsu, Kayoko Arakawa, Ryosuke Sugiyama, Yuichi Suhara, Tetsuya Kusuhara, Hiroyuki
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Drug metabolism and pharmacokinetics
The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in h...
Kanamitsu, Kayoko Arakawa, Ryosuke Sugiyama, Yuichi Suhara, Tetsuya Kusuhara, Hiroyuki
Published in
Drug metabolism and pharmacokinetics
The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in h...
He, Hang Nie, Ya-Li Li, Jiang-Feng Meng, Xiang-Guang Yang, Wei-Hong Chen, Yu-Long Wang, Shu-Jie Ma, Xiaochao Kan, Quan-Cheng Zhang, Li-Rong
...
Published in
Drug metabolism and pharmacokinetics
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 re...
Sasaki, Shotaro Futagi, Yuya Ideno, Masaya Kobayashi, Masaki Narumi, Katsuya Furugen, Ayako Iseki, Ken
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Drug metabolism and pharmacokinetics
In the present study, we demonstrated that monocarboxylate transporter 4 (MCT4) is functionally expressed in Caco-2 cells. We studied the effects of 4 nonsteroidal anti-inflammatory drugs on the uptake of l-lactate as a good substrate of MCT4 by the cells. The monocarboxylate drugs inhibited the uptake of l-lactate into the cells. Diclofenac, as a ...
Uwai, Yuichi Kawasaki, Tatsuya Nabekura, Tomohiro
Published in
Drug metabolism and pharmacokinetics
Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We p...
