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119 巻, 11 号
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伊関 克彦1999 年 119 巻 11 号 p. 787-804
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーThe synthesis of chiral fluorinated molecules is important in the biological and medicinal chemistry fields in view of the influence of fluorine's unique properties on biological activity. In recent years, we have studied asymmetric synthesis focussing on such optically active compounds. This review describes 1) diastereoselective trifluoromethylation of chiral N-acyloxazolidinones, 2) catalytic enantioselective aldol reactions of fluorine-substituted ketene silyl acetals, and 3) catalytic enantioselective allylation of aldehydes mediated by chiral Lewis bases. The trifluoromethylation of lithium enolates of N-acyloxazolidinones with iodotrifluoromethane is mediated by triethylborane to give the corresponding trifluoromethylated products with up to 86% diastereomeric excess. The stereoselective reaction is considered to proceed through the attack of the trifluoromethyl radical on the less hindered face of the lithium imide.Difluoroketene and bromofluoroketene trimethylsilyl ethyl acetals react with various aldehydes in the presence of chiral Lewis acids to afford the corresponding desired aldols with up to 99% enantiomeric excess (ee). It is noteworthy that the aldol reactions of the fluorine-substituted acetals at -78°C and at higher temperatures (-45 or -20°C) provide the (+)- and (-)-aldols, respectively, with excellent-to-good enantioselectivity. Chiral phosphoramides newly prepared from (S)-proline were found to catalyze the allylation and crotylation of aromatic aldehydes with allylic trichlorosilanes in good enantioselective yields (up to 90% ee). (S, S)-Bis(α-methylbenzyl)formamide developed as an efficient catalyst for the allylation and crotylation of aliphatic aldehydes mediates the enantioselective addition with the assistance of hexamethylphosphoramide (HMPA) to afford the corresponding homoallylic alcohols in up to 98% ee.抄録全体を表示PDF形式でダウンロード (1313K) -
酒井 朝也, 野原 大輔, 栗本 英治1999 年 119 巻 11 号 p. 805-821
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーWhen matter assembles to take a shape, there arises a function specific to the shape, and at the same time the value is produced. A shape of matter originates from physics of the constituents combined with the environmental conditions holding the matter. It is convenient for recognition of shape to classify the matter in three categories ; non-living matter, living organic matter and manmade matter. In the case of non-living matter, a process of shape arrangement is clearly understood by means of thermodynamics. It is also distinctly recognized that, in total stabilizing energy of the shape ΔG°, the entropy term TΔS° is responsible for the shape creation. Shape arrangement often proceeds through kinetic regime, in such cases (ΔG°)〓 or T(ΔS°)〓 should be adopted. Synthetical formation of the shape can of course be attained thermodynamically or kinetically. In the case of living organic matter, the creation of the shape depends on evolution, which is undoubtedly based on environmental conditions as well as physical properties of the matter itself. A key compound in shape arrangement of living organic matter is a globular protein. For the formation of the shape of the globular protein, nature uses chaperone while human beings utilize a refolding technique known as an important down-stream art of the recombinant DNA process. Detailed description of the art appears in a text as the course to achieve the quantitative refolding of several globular proteins. The shape of man-made matter keeps the successive creation via evolution operated by the market economics. Formation of the shape is managed skillfully by means of mechanical engineering and/or material sciences. In the last section, some aspects on the possibility of a man-made enzyme are described.抄録全体を表示PDF形式でダウンロード (1823K) -
鈴木 洋史1999 年 119 巻 11 号 p. 822-834
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーThe excretion of drugs mediated by transporters plays an important role in the detoxification of xenobiotics. In this article, I will summarize recent progress we have made in this field, particularly focusing on the roles of transporters responsible for exporting drugs. As far as the biliary excretion of xenobiotics is concerned, it has been suggested that canalicular multispecific organic anion transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) is involved in the ATP-dependent export of organic anions across the bile canalicular membrane. By comparing the transport across this membrane between normal rats and Eisai hyperbilirubinemic rats whose cMOAT/MRP2 function is hereditarily defective, we were able to demonstrate the substrate specificity of cMOAT/MRP2. This includes non-conjugated anionic drugs, and glutathioneand glucuronide-conjugates of xenobiotics. The role of cMOAT/MRP2 in drug disposition has also been clarified. Moreover, the cDNA of cMOAT/MRP2 has been cloned and its functional analysis has been completed. Thus, it may be possible to predict in vivo transport across the bile canalicular membrane from in vitro data using the recombinant transporter. We also cloned MRP3 as an inducible transporter in the liver under the cholestatic conditions. Although MRP3 mediates the cellular export of non-conjugated organic anions and glucuronide-conjugates, the substrate specificity of MRP3 is different from that of cMOAT/MRP2 in that glutathione-conjugates are poor substrates for MRP3. It is possible that MRP3 plays an important role under certain pathological conditions in the liver. Since it has been shown that cMOAT/MRP2 and MRP3 are expressed in the small intestine under physiological conditions, it seems reasonable that these transporters are responsible for the previously reported cellular extrusion of organic anions. We also found that there was MRP activity in the blood-brain and blood-cerebrospinal fluid barriers. RT-PCR resulted in the amplification of MRP1, 5 and 6 from freshly isolated rat cerebral endothelial cells. It has been suggested that there is basolateral localization of MRP1 in the choroid plexus. In conjunction with the P-glycoprotein located on the luminal membrane of cerebral endothelial cells, these transporters play significant roles in restricting the entry of xenobiotics from the circulating blood into the central nervous system. Regulation of the activity of these efflux transporters allows the disposition of drugs to be altered.抄録全体を表示PDF形式でダウンロード (1238K) -
今村 順茂1999 年 119 巻 11 号 p. 835-849
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーIn this review, we describe the physiological, genetic and pathological factors regulating the reductive metabolism of drugs with a ketone group. Acetohexamide (AH) was chosen as a model drug with a ketone group. Species differences of AH reductase activity were observed in liver cytosol and microsomes of animals tested. AH reductase activity in liver microsomes of rats was much higher in males than females. The activity was not detectable until 4 weeks of age after birth in both sexes, but increased markedly at puberty only in males. AH reductase activity in liver microsomes of male rats was decreased by testectomy, and restored by the treatment with testosterone propionate, indicating that the sex-related difference and postnatal development of the activity are regulated by androgens. There was a strain difference of AH reductase activity in liver microsomes of male rats. Of rat strains tested, only Wistar-Imamichi strain was found to lack male-specific microsomal enzyme activity. The inheritance pattern of AH reductase activity in liver microsomes of rats was determined by mating the genetic deficiency Wistar-Imamichi strain with Fischer-344 strain. Streptozotocin-induced diabetes significantly decreased AH reductase activity in liver microsomes of male rats. Furthermore, the physiological role of AH reductase present in liver microsomes of male rats was examined. We propose the possibility that the male-specific microsomal enzyme physiologically functions as a 20β-hydroxysteroid dehydrogenase.抄録全体を表示PDF形式でダウンロード (1419K) -
清水 孝子, 山田 安彦, 田下 明子, 山本 康次郎, 小瀧 一, 澤田 康文, 伊賀 立二1999 年 119 巻 11 号 p. 850-860
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーSarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. Sarpogrelate and its active metabolite (M-1) are potent inhibitors of human platelet aggregation, and selectively inhibit 5-HT2-serotonergic receptors on human platelets. However, the plasma concentrations of these inhibitors do not correlate to the inhibitory effect on platelet aggregation after administration. Sarpogrelate disappears from the plasma more rapidly in comparison to the duration of its pharmacological effect, and the plasma concentration of M-1 is very low (<1/10 of sarpogrelate). In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effects of sarpogrelate and M-1, by considering both the competitive reversible inhibition and the association/ dissociation process of these drugs at the 5-HT2 receptors on platelets (Most data used for analysis were obtained from the literatures, except for the serum protein binding rate of M-1). The developed model was well fitted to the actual data, and suggested that M-1 was more effective for the inhibition of platelet aggregation than sarpogrelate. On the basis of these findings, a new method was developed for predicting inhibitory effects on platelet aggregation after oral administration of sarpogrelate hydrochloride. This method is useful for planning a rational dosage regimen of sarpogrelate hydrochloride and predicting the duration of antiplatelet activity after the discontinuance of the drug.抄録全体を表示PDF形式でダウンロード (872K) -
谷川 浩司, 松本 宜明, 松崎 貴志, 松本 光雄, 福岡 正道, 野口 さおり, 五島 敏郎1999 年 119 巻 11 号 p. 861-867
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーTherapeutic drug monitoring (TDM) of theophylline is essential duties at hospital pharmacy in Japan. The relationship between serum concentrations and clinical effects of theophylline has been investigated. The pharmacokinetics of theophylline was determined from the concentration of theophylline in the serum which were calculated on the basis of TDM for patients administered theophylline. The one-compartment model as a pharmacokinetic model was assumed. The relationship between clinical effects of theophylline and the predicted concentrations calculated using population parameters was evaluated. The obtained parameters are ka(h-1)=0.223, ke(h-1)=0.047(1-0.0025·age(y)(p.o.) and 0.076(1-0.0025·age(y))(d.i.v.), Vd(1/kg)=0.733(p.o.) and 0.830.(d.i.v.). The bioavailability is 0.732, and theophylline/aminophylline is 0.846. The model including no serum creatinine as a variational factor was considered to be best. The following three groups were used as a clinical evaluation; effective as theophylline therapy was 43%, no change of the clinical status after administration of theophylline was 42%, and aggravation after administration of theophylline was 15%. There is no relationship between the predicted concentration using parameters of the final model and these three groups. These results suggest that TDM of theophylline should be assessed in terms of clinical effects and also suggests that in should be kept monitoring from the viewpoint of the prevention of toxic effects in the theophylline therapy.抄録全体を表示PDF形式でダウンロード (667K) -
小里 一友, 三方 比奈子, 鶴森 敏樹1999 年 119 巻 11 号 p. 868-879
発行日: 1999/11/01
公開日: 2008/05/30
ジャーナル フリーA rapid and simple determination of tropane-alkaloids (hyoscyamine, scopolamine) in gastrointestinal drugs was investigated by capillary electrophoresis. Micellar electrokinetic capillary chromatography (MEKC) using a fused silica capillary (560 mm×0.075 mm i.d.) in 0.1 M SDS 20 mM borate buffer (pH 10)/acetonitrile (97 : 3) gave complete separation of the two alkaloids within 40 min. A sample solution was introduced by pressure method (50 mbar, 3.7 s), separation conditions applied voltage 15 kV and on-column detection was performed at 210 nm. Calibration curves for hyocyamine and scopolamine showed a good linearity in the range of 4-12μg/ml(r=0.9970) and 390-1150 ng/ml(r=0.9976). The present method is applicable to the simple and rapid determination of hyoscyamine and scopolamine in commercial gastrointestinal drugs.抄録全体を表示PDF形式でダウンロード (1016K)
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