Garam Han

In vitro metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

1. The metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, was investigated in vitro using human liver microsomes and serum. After 60-min incubation in human liver microsomes with β-nicotinamide adenine dinucleotide phosphate (NADPH) or uridine diphosphate glucuronic acid (UDPGA), the residual KBH-A40 was 90.6% ± 5.1% and 28.9% ± 2.0% (t1/2 = 26 min), respectively, suggesting that KBH-A40 is likely predominantly metabolized by glucuronidation, rather than by cytochrome P450 (CYP)-mediated oxidation. Consistently, KBH-A40 glucuronide was the only metabolite identified following incubations of KBH-A40 with human liver microsomes in the presence of both NADPH and UDPGA. 2. KBH-A40 was not notably degraded when incubated with human serum for 60 min. In contrast, KBH-A40 was rapidly hydrolysed to its carboxylic acid form in rat serum (t1/2 = 13 min). 3. Taken collectively, the results suggest that KBH-A40 is likely metabolized in man predominantly by glucuronidation of its hydroxamic acid moiety, with negligible biotransformation elsewhere in the molecule.

Intrinsic quasi-particle dynamics of topological metallic states

We investigate the intrinsic quasi-particle (QP) dynamics in the topological metallic (TM) states of Bi2Se3, Bi2−xSnxTe3 (x=0.0067) and Sb. Surprisingly, the intrinsic QP dynamics are mostly determined by the scattering within the TM states and are unaffected by the bulk electronic states. We observe the binding energy-independent imaginary part of the self-energy Im Σ for the QPs in the TM states. We attribute the binding energy-independent Im Σ to momentum mixing due to flakes or warped surfaces of the cleaved samples. This makes the intrinsic scattering rate of the QPs extremely small in the TM states. We discuss a few possible contributions to the smallness of the Im Σ for QPs. Our new observations on the extremely small intrinsic QP scattering rates may open up the possibility of room-temperature quantum devices.

Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats.

The pharmacokinetics and metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase inhibitor, were characterized in male Sprague–Dawley rats. KBH-A40 exhibited a high clearance (12.0 ± 2.8 l h−1kg−1), a large volume of distribution at steady state, Vss (3.9 ± 1.5 l kg−1), and a short half-life, t1/2 (2.0 ± 0.3 h). KBH-A40 was rapidly converted to its metabolite, KBH-A40 carboxylate, after intravenous (2 and 20 mg kg−1) and oral (10 mg kg−1) administration; the carboxylate metabolite remained at elevated concentrations in the plasma for more than 8 h. Glucuronide conjugate of KBH-A40 was identified qualitatively by using liquid chromatography tandem mass spectrometry in rat plasma. KBH-A40 was rapidly absorbed (tmax = 0.4 h) after oral dose, consistent with its permeability in Caco-2 cells. Its oral bioavailability was low (14.2–14.8%). An apparent “double peak” phenomenon was observed for both KBH-A40 and KBH-A40 carboxylate after oral administration. KBH-A40 was degraded rapidly by glucuronidation, but not by cytochrome P450-mediated oxidation, in rat liver microsomes. These results suggest that the rapid metabolism of KBH-A40 could be a major reason for its poor pharmacokinetics. Therefore, this work provides valuable structural information to improve pharmacokinetic properties of KBH-A40, a lead compound.

Dxz/yz orbital subband structures and chiral orbital angular momentum in the (001) surface states of SrTiO3

We have performed angle resolved photoemission spectroscopy (ARPES) experiments on the surface states of SrTiO

Oxygen-content-dependent electronic structures of electron-doped cuprates

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Photoemission studies of Cu intercalated NbSe2

(001) using linearly and circularly polarized light to investigate the subband structures of out-of-plane

Interlayer-state-driven superconductivity in CaC6 studied by angle-resolved photoemission spectroscopy

d_{xz/yz}

Structural investigation of the insulator-metal transition in NiS2−xSex compounds

orbitals and chiral orbital angular momentum (OAM). The data taken in the first Brillouin zone reveal new subbands for

Experimental observation of hidden Berry curvature in inversion-symmetric bulk 2H-WSe2

d_{xz/yz}

Pressure-induced metal–insulator transitions in chalcogenide NiS2-xSex

orbitals with Fermi wave vectors of 0.25 and 0.45