Daisuke Nakai
Daiichi Sankyo
PharmacokineticsOrganic anion transporter 1Internal medicineEndocrinologyMolecular biologyEnzymeChemistryIn vivoLaninamivirValproic AcidMetaboliteNeuraminidase inhibitorGlucuronideAPEHMeropenemHydrolaseTivantinibATP-binding cassette transporterBiochemistryMedicineBiologyDrug interactionPharmacology
Publications 24
#1Yumi Nishiya (Daiichi Sankyo)H-Index: 6
#2Eiko Suzuki (Daiichi Sankyo)H-Index: 6
Last. Daisuke Nakai (Daiichi Sankyo)H-Index: 11
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1 CitationsSource
#1Eiko Suzuki (Daiichi Sankyo)H-Index: 6
#2Kumiko Koyama (Daiichi Sankyo)H-Index: 8
Last. Kan Chiba (Chiba University)H-Index: 1
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Background and Objective Human in vitro and dog in vitro/in vivo researches indicate that the drug–drug interaction (DDI) of decreased plasma valproic acid (VPA) concentration by co-administration of carbapenem antibiotics is caused by inhibition of acylpeptide hydrolase (APEH)-mediated VPA acylglucuronide (VPA-G) hydrolysis by carbapenems. In this study, we investigated VPA disposition and APEH activities in TK-NOG chimeric mice, whose livers were highly replaced with human hepatocytes, to eval...
7 CitationsSource
#1Yumi Nishiya (Daiichi Sankyo)H-Index: 6
#2Daisuke Nakai (Daiichi Sankyo)H-Index: 11
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
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Abstract1. In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites.2. The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer ...
4 CitationsSource
#1Eiko Suzuki (Daiichi Sankyo)H-Index: 6
#2Daisuke Nakai (Daiichi Sankyo)H-Index: 11
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
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Abstract1. Our previous in vitro studies suggest that inhibition of the acylpeptide hydrolase (APEH) activity as valproic acid glucuronide (VPA-G) hydrolase by carbapenems in human liver cytosol is a key process for clinical drug–drug interaction (DDI) of valproic acid (VPA) with carbapenems. Here, we investigated whether in vivo DDI of VPA with meropenem (MEPM) was caused via inhibition of APEH in dogs.2. More rapid decrease of plasma VPA levels and increased urinary excretion of VPA-G were obs...
11 CitationsSource
#1Tsuyoshi Mikkaichi (Daiichi Sankyo)H-Index: 8
#2Daisuke Nakai (Daiichi Sankyo)H-Index: 11
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
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Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are key molecules that are involved in hepatic uptake related to drug elimination, and OATP-mediated drug interactions are of clinical concern. In this study, with an aim to determine a cutoff value for the potential involvement of OATP, we collected data on the distribution of 12 human OATP and 24 non-OATP radiolabeled substrates in rats. The OATP substrates exhibited a higher tissue-to-plasma ratio (Kp) in the liver than that in the oth...
6 CitationsSource
#1Yumi Matsui (Daiichi Sankyo)H-Index: 6
#2Takahiro Yamaguchi (Daiichi Sankyo)H-Index: 3
Last. Kazuhiko Tamaki (Daiichi Sankyo)H-Index: 9
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Abstract To obtain potent liver X receptor (LXR) agonists, a structure–activity relationship study was performed on a series of tert -butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improve...
6 CitationsSource
#1Takahiro Murai (Daiichi Sankyo)H-Index: 4
#2Hideo Takakusa (Daiichi Sankyo)H-Index: 7
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
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Abstract1. The biotransformation and disposition of tivantinib in humans, dogs and rats was examined after a single oral administration of [14C]tivantinib. Tivantinib constituted no more than one-third of the plasma radioactivity in all species, demonstrating significant contribution of the metabolites to plasma radioactivity. The major circulating metabolites in all species were M4 and M5, hydroxylated metabolites at the benzyl position of the tricyclic ring, accounting for 19.3 and 12.2% of th...
9 CitationsSource
#1Kumiko Koyama (Daiichi Sankyo)H-Index: 8
#2Yuji Ogura (Daiichi Sankyo)H-Index: 5
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
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Laninamivir octanoate (LO) is an octanoyl ester prodrug of the neuraminidase inhibitor laninamivir. After inhaled administration, LO exhibits clinical efficacy for both treatment and prophylaxis of influenza virus infection, resulting from hydrolytic bioactivation into its pharmacologically active metabolite laninamivir in the pulmonary tissue. In this study, we focused on the identification of LO-hydrolyzing enzymes from human pulmonary tissue extract using proteomic correlation profiling—a tec...
9 CitationsSource
#1Hidetoshi FuruieH-Index: 3
#2Kaoru Toyama (Daiichi Sankyo)H-Index: 4
Last. Hitoshi Ishizuka (Daiichi Sankyo)H-Index: 9
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Background: A single inhaled dose of LO, a long-acting neuraminidase inhibitor, exhibits efficacy to patients with influenza virus infection. However, the relation between PK and its long-lasting efficacy has not fully been investigated. Purpose: Intrapulmonary PK in healthy volunteers and the intracellular drug disposition in mice were evaluated to support its long-lasting efficacy. Methods: Each subject underwent bronchoalveolar lavage (BAL) at specified time intervals from 4 to 240 hrs after ...
#1Keiji Saito (Daiichi Sankyo)H-Index: 3
#2Akira Nakao (Daiichi Sankyo)H-Index: 5
Last. Satoru Naito (Daiichi Sankyo)H-Index: 5
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Abstract A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3- b ]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduct...
22 CitationsSource