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In addition to the attention focused on drug/drug interactions such as those in drug distribution, drug metabolism, drug absorption, and receptor binding in multiple-drug therapy, [1][2][3][4] drug/metabolite interaction(s) in the biopharmaceutical fate of drugs was reported.5-10) Studenberg and Brouwer reported that the metabolites of phenobarbital inhibited the biotransformation of acetaminophen (APAP).11) We also reported the effects of the concomitant use of N-acetyl-paminophenol O-sulfate (APAPS, as potassium salt) [12][13][14] and its geometric isomers 15) with their parent drug, APAP. In those reports, it was found that the tissue-to-plasma concentration ratio (K p ) of APAP was significantly increased in the liver, heart, kidney, and brain in the presence of APAPS but not by its geometric isomers. That is, APAPS appears to play a role as a biodistribution promoter. A similar phenomenon was observed when 4-hydroxyantipyrine was concomitantly administered with antipyrine.16) The evaluation of glu-17,18) as a biodistribution promoter was also carried out with verapamil hydrochloride and tegafur. 19) In this paper, another example using GSO 3 Na with thiopental sodium is described. MATERIALS AND METHODSMaterial GSO 3 Na was prepared in our laboratory as below. Thiopental sodium was kindly supplied by Tanabe Seiyaku Co., Ltd. (Osaka, Japan). Glutathione (GSH) was dissolved in an isotonic phosphate buffer solution (pH 7.4). Thiopental sodium and GSO 3 Na were dissolved in saline before use. All chemicals and reagents were commercially available and of analytical grade or better.Preparation of GSO 3 Na: GSO 3 H (free acid) was prepared from GSH by the method of Calam and Waley.17) A solution of 1.1 g of GSO 3 H in 3 ml of water was neutralized by saturated NaHCO 3 aqueous solution and the resulting solution was evaporated to dryness. The residue was triturated with methanol. The insoluble crystalline solid (GSO 3 Na) gave a single spot on TLC in several solvent systems and was pure enough for use in the following experiments. Analytical data are also consistent with its structure, mp 209-211°C (dec.), yield 1.1 g (overall yield from GSH was 85%). Anal. Calcd for C 10 H 15 Na 2 N 3 O 9 S · 1.5H 2 O: C, 28.18; H, 4.26; N, 9.86. Found: C, 28.08; H, 4.07; N, 9.63. Animals Male Wistar rats (220-380 g) (Japan SLC, Hamamatsu, Japan) were used.In Vivo Experiments The rats were fasted overnight before use, but allowed free access to water, and were fixed in the dorsal position under urethane anesthesia (900 mg/kg, i.p.). Polyethylene tubing was cannulated into both the left femoral vein and the right femoral artery.Effect of GSO 3 Na and GSH on Pharmacokinetic Parameters of Thiopental Sodium: GSO 3 Na and GSH were intravenously administered at an initial dose (29.4, 174.5 mg/kg, respectively), followed by constant infusion (300, 125.8 mg/ (kg · h), respectively) to maintain the target plasma concentration (400, 50 mg/ml, respectively) through a cannula in the left femoral vein throughout the experiment. Thiopental sodiu...

Streptomyces lividans FtsY (SlFtsY) was cloned and overexpressed in Escherichia coli. Analysis of the amino acid (aa) sequence showed a concentration of hydrophilic aa's in the N-terminal half region of SlFtsY as observed in that of E. coli FtsY (EcFtsY). However, the length of the hydrophilic region was shorter in SlFtsY than in EcFtsY. Overexpression of SlFtsY in E. coli resulted in growth suppression as in the case of the overexpression of EcFtsY, while growth suppression as a result of the overexpression of the C-terminal half region of SlFtsY was limited. This result suggests that the N-terminal hydrophilic region of SlFtsY, regardless of its short length, would behave like its counterpart region of EcFtsY in E. coli.

Under normal physiologic conditions the receptor for F. VIII/VWF on human platelets is not readily available unless the antibiotic, ristocetin, is added. Searching for a physiologic mechanism inducing the receptor for F. VIII/VWF on human platelets, we found that low doses of thrombin (0.01-0.05 U/ml) induce steady state binding of 125I- F. VIII/VWF to human platelets. The binding is saturable and specific. Specificity was established by demonstrating that 100-fold molar excess of unlabeled F. VIII/VWF inhibited the binding while an excess of fibrinogen or fibro- nectin, two common contaminants of F. VIII/VWF, did not inhibit binding of 125I-F. VIII/VWF. Furthermore, rabbit antibody against F. VIII inhibited the binding. Thrombin- induced binding to human platelets can be observed only with fresh, metabolically active platelets. Glutaralde- hyde-treated platelets did not bind 125I-F. VIII/VWF following their treatment with thrombin, although they exhibited good binding in the presence of ristocetin. Thrombin appears to induce binding by acting on platelets rather than on F. VIII/VWF itself. Prostacyclin (PGI2 10-9M) inhibited thrombin-induced binding of 125I-F. VIII/VWF to human platelets, while ritcocetin-induced binding remained unaffected. Strikingly, PGI2-induced inhibition of binding was observed not orly when PGI2 was added before thrombin but also when PGI2 (10-9 M) was used 30 minutes after thrombin treatment and addition of 125I-F. VIII/VWF. Thus, binding of F. VIII/VWF to platelet receptor is induced by low concentrations of thrombin and is inhibited by PGI2. Since both agents are generated in the vicinity of injured vessel wall they may contribute to platelet-F. VIII/VWF- vessel wall interaction in vivo by regulating “up and down” platelet receptor for F. VIII/VWF.