Masahisa Hashimoto

Simultaneous determination of plasma and urinary uric acid, xanthine, hypoxanthine, allopurinol, oxipurinol, orotic acid, orotidine and creatinine by high-performance liquid chromatography

Abstract A new high-performance liquid chromatographic procedure is described for the simultaneous determination of plasma and urinary uric acid, xanthine, hypoxanthine, allopurinol, oxipurinol, orotic acid and orotidine whose quantities are varied by allopurinol treatment in man. Creatinine was also measurable. The method was established by high-performance liquid chromatography and gas chromatography—mass spectrometry.

Autoradiographic and biochemical studies of drug distribution in the liver. II. [35S]Chlorpromazine and [14C]imipramine.

SummaryWhole body autoradiography revealed that the distribution pattern of [35S]chlorpromazine and [14C]imipramine in the mouse and rat liver was heterogeneous (or reticular) shortly after intravenous administration of the labeled agents and then became homogene-ous. Microautoradiography by dry-mounting method revealed that the macroscopic heterogeneous pattern of [35S]chlorpromazine was due to its periportal localization in the hepatic lobule.The present studies indicated that the heterogeneous distribution was re-arranged to a homogeneous one in the following way: 1. The amount of [35S]chlorpromazine and [14C]imipramine circulated to the liver was greatly restricted by their significant distribution in non-hepatic tissues shortly after administration. This was shown by whole body autoradiography, radiometry of tissues and volumes of distribution in non-hepatic tissues. Therefore, 2. perilobular hepatocytes alone could take up the agents and consequently, centrilobular cells were unavailable to them: heterogeneous distribution pattern is formed. This was shown by microautoradiography described above, and by the rapid and significant uptake of the agents by isolated hepatocytesin vitro and of [35S]chlorpromazine by the liver to which the agent was continuously administeredin situ. However, 3. re-distribution of [35S]chlorpromazine and [14C]imi-pramine occurred thereafter. Therefore, the radioactive compounds were significantly supplied to the liver late after administration: the pattern became homogeneous. This was shown by the whole body autoradiography and radiometry.

Autoradiographic and biochemical studies of drug distribution in the liver III. [14C] Aminotriazole

SummaryWhole body autoradiography revealed that the distribution pattern of [14C]aminotriazole in the mouse liver was homogeneous after intravenous administration of the labeled agent and then became heterogeneous (or reticular). Microautoradiography by dry-moun-ting method revealed that the macroscopic heterogeneous pattern was due to the central localization of the radioactive compound in the hepatic lobule.The present studies indicated that the heterogeneous distribution could be explained as follows. The amount of [14C]aminotriazole circulated to the liver was large since the compound was not so significantly distributed in non-hepatic tissues: distribution pattern was homogeneous in the liver. This was shown by whole body autoradiography and radiometry of tissues. A part of [14C]aminotriazole radioactivity present in the liver was gradually bound covalently to hepatic macromolecules. This was shown by whole body autoradi-ography after whole body sections of the mouse were extracted by acid, and by the biochemical fractionation of the liver. The cova-lently bound radioactivity alone became apparent in centrilobular hepatocytes: the distribution was heterogeneous. This was shown by microautoradiography and by the finding that the elimination rate of the bound radioactivity was slower than that of unbound radioactivity.

[Syntheses of [prolyl-U-14C]alacepril and its related compounds].

In order to study the metabolic fate of alacepril, an anti-hypertensive agent, the 14C-labeled compound of alacepril and its related compounds were synthesized. [Prolyl-U-14C]alacepril was synthesized in over-all yield of 32.7-38.0% by the mixed anhydride condensation of L-phenylalanine with [prolyl-U-14C]DU-1163, which had been prepared from L-[U-14C]proline and N-(S-3-acetylthio-2-methylpropanoyloxy)succinimide. [Prolyl-U-14C]captopril and [prolyl-U-14C]DU-1227 were prepared in high yields by hydrolysis of [prolyl-U-14C]DU-1163 and [prolyl-U-14C]alacepril, respectively. [Prolyl-U-14C]captopril-cysteine was synthesized by condensation of [prolyl-U-14C]captopril with cystine S-monoxide in 55.0% yield.