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M Yabuki

Publications and source records attributed to M Yabuki.

60 records · Page 4Linked to original sources
PubMedDate not supplied

Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849) in rats.

Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849), a novel immunomodulatory agent, in rats was investigated. By co-chromatography with authentic samples, desmethylated (SM-8800) p-hydroxylated (SL-5512) and desmethylated-p-hydroxylated SM-8849 (SL-5515) were detected in the bile. Thermospray mass spectrometry (TSP-MS) analysis of five metabolites isolated from the bile revealed molecular ions of both conjugates (glucuronides and a sulfate) and their aglycones. Aglycone structures were determined by comparison of their product spectra with those of authentic standards. Further analyses of conjugation sites were carried out by 1H-NMR including differential NOE. As a result, the sulfate of SL-5515 (5515-S), the N-glucuronides of SL-5512 and SM-8849 (5512-NG and 8849-NG, respectively), the glucuronide of SL-5512 (5512-G) and the O-glucuronide of 4-hydroxy-3-methoxy-SM-8849 (CatOMe-OG) were identified. In addition, N-methylthiouras was identified in urine by LC/MS/MS.

Adjuvants, Immunologic↗
PubMedDate not supplied

Effect of HSP70 induced by warm ischemia to the liver on liver function after partial hepatectomy.

BACKGROUND/AIMS: The purpose of this study was to determine if induction of HSP70 (heat shock protein 70), a stress protein which plays a cytoprotective role in response to various stimuli, protects hepatocytes from damage caused by partial hepatectomy and, if so, to elucidate the mechanism of such protection. METHODOLOGY: One hundred and eight male F344 rats weighing 190-220 g were randomly assigned to two groups with or without the presence of preconditioning. Fifteen-minute warm ischemia was applied to the liver of rats to induce HSP70, and 70% hepatectomy was performed 48 hours after the induction of HSP70 (ischemia group; n = 72). The rats in the nonischemia group did not undergo 15-min warm ischemia prior to 70% hepatectomy (nonischemia group; n = 36). Six rats, selected randomly from each group, were sacrificed at each measurement point to obtain blood and liver tissue samples. The levels of HSP70 in the liver, serum nitric oxide, levels of catalase and superoxide dismutase activity in the liver as antioxidative enzymes, and levels of Bcl-xL and Bax proteins and caspase-3-like activity in the liver as indices of apoptosis, were measured. RESULTS: The mean +/- SD level of HSP70 in the ischemia group (100 +/- 42 arbitrary unit (au)) was significantly higher than that of the nonischemia group (2 +/- 0.7 au) immediately before hepatectomy (P < 0.05). The ischemic preconditioning attenuated the liver damage caused by the subsequent partial hepatectomy. The levels of superoxide dismutase and catalase activity, serum nitric oxide level, and Bax protein level of the ischemia and nonischemia groups showed no significant differences after the partial hepatectomy. In contrast, the mean +/- SD level of Bcl-xL in the liver of the ischemia group (261 +/- 52 au) was significantly higher than that in the nonischemia group (114 +/- 33 au) 12 hours after the hepatectomy (P < 0.01). Furthermore, the mean +/- SD level of caspase-3-like activity in the liver of the ischemia group (18.1 +/- 4.6 au) was significantly lower than that of the nonischemia group (26.0 +/- 4.8 au) at 12 hours after the hepatectomy (P < 0.05). CONCLUSIONS: HSP70 induced by ischemic preconditioning prior to the partial hepatectomy was considered to protect the liver itself. In addition, the induced HSP70 may affect the Bcl-xL level after partial hepatectomy. Therefore, Bcl-xL seems to be involved in the reduction of liver damage after partial hepatectomy along with HSP.

Alanine Transaminase↗
PubMedDate not supplied

Pharmacokinetics of SM-10888 and its metabolites depending on their physicochemical properties.

To investigate how the physicochemical properties and pharmacokinetics of SM-10888 are altered by metabolic reactions, physicochemical and pharmacokinetic parameters of its phase I and phase II metabolites were determined. The metabolic pathways of SM-10888 in rats include oxidation at the C1 position (via the hydroxylated metabolite M3 to the cyclic ketone M4) and glucuronidation of both SM-10888 and M3 (SMG and M3G). Partition coefficients between n-octanol/pH 7.4 buffer (logP*) were determined to be 2.23 for SM-10888, 1.59 for M3, 2.66 for M4, -1.37 for SMG, and -1.72 for M3G. The phase I metabolite M3 showed lower lipophilicity and serum protein binding at pH 7.4, and larger renal clearance (CLr) than SM-10888. In contrast, the further oxidized metabolite M4 demonstrated higher lipophilicity and protein binding and lower CLr than SM-10888 and M3. Among these nonconjugated forms, only the pKa value of M4 was found to be below 7.4 (6.2 for M4, 8.5 for SM-10888, and 8.0 for M3), indicating that M4 exists in a more lipophilic nonionized form at the physiological pH, whereas SM-10888 and M3 are present as ionized forms. The significant shift in pKa of M4 could be the result of a cooperative effect of the electron withdrawing carbonyl group and resonating structure allowing hydrogen bond formation between CO and NH2 group, and might explain its high lipophilicity and low CLr. Glucuronidation significantly increased hydrophilicity with CLr's in excess of the glomerular filtration rate, suggesting involvement of active transport.

Aminacrine↗