The liver is the major organ involved in the metabolism and elimination of xenobiotics. Evaluating accurately hepatic clearance is very important for predicting the pharmacological effect and/or side-effects of drugs, as well as changes in drug disposition during disease. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carriermediated transport contributes to hepatic uptake and/or biliary excretion. In particular, primary active transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. We have found that a rate-limiting step for several drugs in terms of the hepatic clearance was the membrane transport process. For these drugs, such a saturable transport process can be one of the major determinants which influence not only hepatic clearance itself but also disposition (in other words, plasma elimination) in the whole body. We reviewed the carrier-mediated transport mechanisms involved in the hepatic uptake and biliary excretion processes, the multiplicity of transport systems, and further, the physiological meaning of these complex transport systems in the body.
Physicochemical properties of polymorphism of 3, 9-bis-(N, N-dimethylcarbamoyloxy)-5H-benzofuro [3, 2-c] quinoline-6-one (KCA-098) have been investigated. The existence of four crystalline forms (designated as hydrate, I, II and III) was confirmed by X-ray powder diffraction, IR spectroscopy and thermal analysis (DSC and TG). The hydrate was found to be a monohydrate by elemental analysis and water content measurement. DSC measurement found that the hydrate was transformed fo form III at about 93°C, and then to form II at about 152°C, and finally to form I at about 260°C. On the other hand, when suspended in water the forms I, II and III were transformed into hydrate. The transition rate from form III to hydrate was higher than those from form II to hydrate and from form I to hydrate. Form III as a metastable form showed higher solubility than any of form I, II and hydrate.
We have prepared a specific anti-secretin antiserum and developed a sensitive time-resolved fluoroimmunoassay (TR-FIA) for secretin. An anti-secretin antiserum was produced in rabbit by immunization with synthetic secretin C-terminal 8 residue conjugate to chicken serum albumin as antigen. The TR-FIA was based on the competition between free secretin and biotinylated secretin as a tracer for rabbit anti-secretin antibodies on a goat anti-rabbit IgG antibody coated microtiter plate. After separation of bound and free fractions, a solution of europium (III) ion chelate labeled streptavidin (Eu-SA) was added to the biotinylated secretin bound on the microtiter plate. The microtiter plate was washed and then Eu-SA activity was measured by time-resolved fluorometry. In this TR-FIA, the measurable range of secretin was from 2.5 to 100pg/assay and the specificity was less than 0.01% against other peptide hormones. For the measurement of secretin in the human plasma, a sample was required for the pretreatment in order to separate from interfering substances. The mean recovery of secretin using commercially reversed phase column was 80.2% (n=11). The plasma secretin concentrations of normal subjects and those with various diseases could be measured by this proposed TR-FIA.
In order to characterize the chemical change of their constituents during the processing of various Rehmanniae Radixes, we have investigated the constituents by comparing with those of Chinese Juku-jio (variously processed root of Chinese Rehmannia sp.), Korean Kan-jio (dried root of Korean Rehmannia sp.) and each two species of Japanese Sho-jio (fresh root), Japanese Kan-jio (dried root), and Japanese Juku-jio (steamed root), prepared from Rehmannia glutinosa LIBOSCH. var. purpurea MAKINO (Akaya-jio in Japanese) and Rehmannia glutinosa LIBOSCH. forma hueichingensis HSIAO (Kaikei-jio in Japanese). It was found that, during the processing for preparing Kan-jio and Juku-jio from Sho-jio, jio-serebroside (9) and acteoside (10) were provided, and that the iridoid glycosides were completely degradated or their contents decreased remarkably. Quantitative analysis by means of gas liquid chromatography (GLC) has confirmed that the contents of monosaccharides and oligosaccharides in Kan-jio and Juku-jio increased more than those in Sho-jio. During the course of these studies, a new iridoid glycoside named 6'-O-acetylcatalpol (2) was isolated from Japanese Sho-jio and the structure has been determined.
When N-alkylpyridinium derivatives were reduced with sodium borohydride-nickel (II) chloride reduction system, reductive cleavage occurred at the CN bond in the pyridine ring of N-alkylpyridinium derivatives to give a small amount of reductive cleavage product along with the major perhydrogenated product. It was presumed in the previous report that this reductive cleavage in the pyridine ring proceeded through a complex of nickel ion and 1, 2, 3, 6-tetrahydropyridine derivatives produced with NaBH4 alone reduction. The abundances of these reductive cleavage products arising from N-alkylpyridinium derivatives, i.e., paraquat, diquat and so on, are capable of giving a bad effect on the accuracy of gas chromatographic analysis. For the purpose of inhibition of the reductive cleavage in this reduction system, a suitable catalyst was examined. In addition, we pursued whether borane-1, 2, 3, 6-tetrahydropyridine derivative complexes arose from N-alkylpyridinium derivatives by NaBH4 alone reduction or not, and whether these boraneamine complexes were the precursors of reductive cleavage products or not. N-Alkyl-1, 2, 3, 6-tetrahydropyridine derivatives (III-I, IV-I, VI-I, VII-I and VIII-I) and the corresponding borane-amine complexes (III-II, IV-II, VI-II, VII-II and VIII-II) were synthesized by NaBH4 reduction in aqueous solution of N-alkylpyridinium salts, i.e. I, II, 1, 4-dimethylpyridinium iodide (III), 1-dodecylpyridinium chloride (IV), 1, 1'-diethyl-4, 4'-dipyridinium dichloride (V), 1-methyl-4-phenylpyridinium iodide (VI), 1-n-propylpyridinium iodide (VII) and 1-n-butylpyridinium iodide (VIII). The structure of the borane-amine complexes were proved by the Mass spectrometry and 1H-and 13C-NMR analysis. The NiCl2-NaBH4 reduction of the borane-amine complexes gave the perhydrogenated products alone, but not reductive cleavage products. In conclusion, it was recognized that the precursors of reductive cleavage products were not borane-amine complexes, but 1, 2, 3, 6-tetrahydropyridine. Furthermore, it was found the reductive cleavage at the C-N bond in the pyridine ring of these 1, 2, 3, 6-tetrahydropyridine derivatives was hindered by applying Amberlite-Ni2B, NaBH4 reduction system.
The two mono-hydroxylated metabolites of 9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopenta [b] quinoline monohydrochloride monohydrate (NIK-247), which is a new drug for the treatment of dementia, were synthesized to determine their chemical structures. Reduction of two tricyclic ketones, 9-amino-1, 2, 3, 5, 6, 7-hexahydro-8H-cyclopenta [b] quinolin-8-one and 9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopenta [b]-quinolin-1-one, with NaBH4 afforded the corresponding racemic alcohols. The optically active mono-hydroxylated metabolites, (+)-9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopenta [b] quinolin-8-ol and (+)-9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopenta [b] quinolin-1-ol, were obtained by optical resolution of each racemic alcohol using (+)-di-p-toluoyl-D-tartaric acid.
The two dihydroxylated metabolites of 9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopenta [b] quinoline monohydrochloride monohydrate (NIK-247), which is a new drug for the treatment of dementia, were synthesized to determine their chemical structures. Reduction of the tricyclic diketone, 9-amino-2, 3, 6, 7-tetrahydro-1H-cyclopenta [b] quinoline-1, 8 (5H)-dione, with equivalent molar of NaBH4, afforded the racemic two alcohols, (±)-9-amino-2, 3, 5, 6, 7, 8-hexahydro-8-hydroxy-1H-cyclopenta [b] quinolin-1-one and (±)-9-amino-2, 3, 5, 6, 7, 8-hexahydro-1-hydroxy-1H-cyclopenta [b] quinolin-8-one. (+)-9-Amino-2, 3, 5, 6, 7, 8-hexahydro-8-hydroxy-1H-cyclopenta [b] quinolin-1-one was obtained by optical resolution of the corresponding racemic hydroxyketone using (-)-di-p-toluoyl-L-tartaric acid. The optically active dihydroxylated metabolites were obtained by reduction of the (+)-8-hydroxy-1-one with NaBH4.