Carrier-mediated active transport of the glucuronide and sulfate of 6- hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into rat liver: quantitative comparison of permeability in isolated hepatocytes, perfused liver and liver i

ABSTRACT The hepatic uptake of glucuronic acid and sulfate conjugates of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A 2 synthetase, was investigated in rats. The biliary excretion clearance values for the glucuronide and the sulfate, obtained after i.v. administration of E3040, were similar and corresponded to approximately 30% of the hepatic blood flow rate. The influx clearance values of E3040 conjugates in the presence of 3% bovine serum albumin, measured by a multiple indicator dilution method in the perfused liver, were 1.20 ml/min/g liver for the glucuronide and 0.74 ml/min/g liver for the sulfate, which were twice and equal to the normal hepatic plasma flow rate, respectively, which suggests the presence of an efficient transport system(s). The uptake of E3040 conjugates into the isolated hepatocytes is mediated by Na ϩ -independent active transport system(s), which is inhibited by dibromosulfophthalein and bile acids. The uptake for the sulfate had high-affinity and high-capacity transport activity (K m ϭ 25 M; V max ϭ 7.8 nmol/min/10 6 cells) compared with that for the glucuronide (K m ϭ 59 M; V max ϭ 2.2 nmol/min/10 6 cells). The uptakes of E3040 conjugates (glucuronide, sulfate) exhibited a mutual competitive inhibition. It is suggested that both conjugates share a multispecific organic anion transporter located on the sinusoidal membrane. Conjugative metabolism, such as glucuronidation and sulfation, is an important pathway for the inactivation or detoxification of xenobiotics. On the other hand, conjugative metabolites of certain drugs with pharmacologically active (such as the 6-glucuronide of morphine; In previous studies, we reported the disposition of glucuronide and sulfate of E3040, a novel dual inhibitor of 5-lipoxygenase and thromboxane A 2 synthetase, after administration Received for publication May 24, 1996. ABBREVIATIONS: E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; [ C]E3040, [2- 14 C]6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole dihydrochloride; SD rats, Sprague-Dawley rats; DBSP, dibromosulfophthalein; HEPES, N-2-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid; MID method, multiple indicator dilution method; HPLC, high-performance liquid chromatography; BSA, bovine serum albumin; TLC, thin-layer chromatography; AUC ϱ , the area under the plasma concentration-time profiles from zero to infinity; CL bile , the biliary excretion clearance; CL renal , the urinary excretion clearance; CL u,renal , the unbound urinary excretion clearance; X bile , the amount excreted into the bile; X urine , the amount excreted into the urine; CL tot , the total body clearance; PS inf , the influx clearance; PS u,inf , the unbound influx clearance; K inf , the influx rate constant; K eff , the efflux rate constant; K seq , the sequestration rate constant; K m , Michaelis constant; V max , maximal uptake rate; P dif , the nonspecific uptake clearance; LUR, the first-pass liver uptake ratio; UWL, the unstirred water layer; PCMBS, p-chloromercuriphenylsulfonic acid; DIDS, 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid; FCCP, carbonyl cyanide-p-(trifluoromethoxy)-phenylhydrazone; C/M, cell-to-medium concentration

ドイツ ニ オケル ダイガク トウチ ト シゲン ハイブン ガクナイ デノ サンテイシキ ト ギョウセキ キョウテイ ヲ チュウシン ニ

論説Opinionわが国の大学改革では，国立大学の学内ガバナンス改革が重要な論点の1つとなっている．但し，これまでは学長のリーダーシップ強化に注意が偏り，全学の意思決定構造の改革にはあまり関心が向けられなかった．本稿は，学内資源配分を梃子とした本部・部局間関係を考察する材料として，ドイツの州立大学における学内資源配分の方法論から学内ガバナンス体制を考察する．その結果，日本との大きな相違として，ドイツでは基本的に分権的な学内統治体制をとっている点が明らかになった．部局に一定の経営的独立を認め，本部は間接的な統制を行う体制である．そのなかで，算定式（数値指標）や業績協定が分権制を維持する統制ツールとして利用されている．ドイツの事例は，大学内を活性化し，同時に高等教育において経営管理的要素の強化と学術の自律をいかに両立させるかを考えるうえで，1つの解を提供しているIn the discussion about higher education reform in Japan, one of the intensely debated issues is how to reform internal governance of the national universities. The issue of governance has often been reduced to specific problems such as strengthening the president's leadership, while other important topics, particularly streamlining the institutional decision-making structure, have failed to be duly dealt with. By way of a contribution to the debate, this paper investigates the governance structures in German state universities, focusing on the relationships between central management and departments by means of internal resource allocation. This paper shows that German universities basically rely on decentralized governance structures, in which the departments enjoy a certain degree of managerial independence and the university leadership keeps indirect control on them. Steering tools such as formulae (metrics) and performance agreements are employed to serve this decentralized structure. The German model of internal university governance will give us clues to consider how to stimulate teaching and research in the university and, and at the same time, to make compatible managerial components and academic autonomy in higher education