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  • 1
    Electronic Resource
    Electronic Resource
    Renin Inhibitor: Relationship Between Molecular Structure and Oral Absorption (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1443-1447 
    Details
    ISSN: 1573-904X
    Keywords: renin inhibitor ; cyclodextrin ; intestinal permeability ; in situ intestinal loop ; oral absorption ; first pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Common problems in developing renin inhibitors are low solubility, insufficient oral absorption, and fast hepatic clearance. We focused on the molecular structure of renin inhibitors to overcome these problems. Cyclodextrins (CD) improved the low solubility of renin inhibitors, with β-CD showing the best ability to dissolve renin inhibitors. The intestinal absorption of renin inhibitors varied with both their solubility and molecular structure. Coadministration of β-CD improved the intestinal absorption of some renin inhibitors with low solubility as measured by transport into the mesenteric vein in the absorption experiment using the rat intestinal loop. Substitutions at both the N and C terminals was essential for absorption from the small intestine. A naphthyl group at the N-terminal further improved intestinal absorption. A carrier system appeared to be involved in the intestinal absorption of some renin inhibitors. N-methylation at the amide bond of thiazolylalanine suppressed the high hepatic clearance of one of the test compounds 18 which was well absorbed from the small intestine and it improved its oral bioavailability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018948007419
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  • 2
    Electronic Resource
    Electronic Resource
    Renin Inhibitor: Transport Mechanism in Rat Small Intestinal Brush-Border Membrane Vesicles (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1448-1451 
    Details
    ISSN: 1573-904X
    Keywords: renin inhibitor ; rat intestinal brush-border membrane vesicle ; BBMV ; proton coupled uphill transport ; peptide carrier system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The transport characteristics of the renin inhibitor ((3S,4S)-4-[N-morpholinoacetyl-(l-naphthyl)-L-alanyl-N-methyl-(4-thiazolyl)-L-alanyl]amino-3-hydroxy-5-cyclohexyl-l-(4-pyridyl)-l-pentanone; CH3-18) in rat small intestinal brush-border membrane vesicles (BBMV) were examined by a rapid filtration technique. The uptake of CH3-18 was markedly stimulated by an inwardly directed H+ gradient (pH 7.5 inside, pH 5.5 outside) and showed an uphill transport. It was competitively inhibited by tripeptides and tetrapeptides, but not by amino acids or dipeptides. A countertransport effect on the uptake of CH3-18 was observed in the vesicle preloaded with a tripeptide. Effects of the fragments of several renin inhibitors were evaluated by their inhibitory and countertransport effects on the uptake of CH3-18. The morpholino group at the N-terminal was found to be important for the uptake of CH3-18.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018900124257
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Transport Characteristics of S-1090, A New Oral Cephem, in Rat Intestinal Brush-Border Membrane Vesicles (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1488-1492 
    Details
    ISSN: 1573-904X
    Keywords: S-1090 ; transport ; brush-border membrane ; oligopeptide ; histidine ; oral cephem
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Elucidating the transport characteristics of S-1090, a new orally active cephalosporin in rat small intestinal brush-border membranes. Methods. A rapid filtration technique. Results. The uptake of S-1090 was stimulated by an inwardly directed H+-gradient, but did not show overshooting uptake. To investigate the transport system, the inhibitory and countertransport effects of various compounds on S-1090 uptake were examined. Although the dipeptides and tripeptides composed of amino acids with aliphatic side chains did not inhibit the uptake of S-1090, those having histidine, proline or tryptophan as the N-terminal amino acid showed an inhibitory effect. Among the oral cephems tested, ceftibuten showed marked inhibition, while cefaclor and cephalexin had no inhibitory effect. Countertransport effects on S-1090 uptake were observed only when the vesicles were preloaded with histidyl peptides such as His-Gly or His-Ala, while other compounds which exhibited inhibition had no countertransport effect. Conclusions. Based on the above results, there seems to be heterogeneity (multiplicity) in the oligopeptide transport system which may depend on the structure of the N-terminal amino acid. S-1090 may be dominantly transported via a system that recognizes peptides having histidine as the N-terminal amino acid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016287421436
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  • 4
    Electronic Resource
    Electronic Resource
    Development of Anti-Influenza Virus Drugs I: Improvement of Oral Absorption and In Vivo Anti-Influenza Activity of Stachyflin and Its Derivatives (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1041-1046 
    Details
    ISSN: 1573-904X
    Keywords: influenza ; oral absorption ; PEG ; phosphate ester prodrug ; anti-influenza virus drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Stachyflin and its derivatives which are active against the influenza virus in vitro, were studied to improve their reduced in vivo activity after oral administration by chemical modification and some vehicles. Methods. The solubility was examined for different vehicles. The improvement of gastrointestinal absorption was evaluated by the plasma concentration after oral administration to mice or the in situ loop method with rats. The in vivo anti-influenza activity was examined using mice infected with the influenza virus and evaluated based on the virus titer in the lung by TCID50. Results. PEG 400 showed the highest solubility of Stachyflin and its derivative among the vehicles studied. While no viral inhibition was found in the lung after oral administration of 0.5% HPMC suspension of Stachyflin, in vivo anti-influenza virus activity was found with the PEG 400 solution. The absorption of Stachyflin by PEG 400 showed about a fifty-fold increase in AUC compared with that of 0.5% HPMC suspension. Improving the oral absorption of Stachyflin led to an increase in the in vivo anti-influenza virus activity. When the Stachyflin derivative in PEG 4000 was administered orally, there was more enhancement of the oral absorption than with PEG 400. When the aqueous solution of the phosphate ester prodrugs of Stachyflin and its derivative was administered orally, the absorption of the parent compound was improved and in vivo anti-influenza virus activity was found. Conclusions. When Stachyflin and its derivatives were administered orally to mice with a solution in PEG and an aqueous solution of their phosphate ester, their oral absorption was improved and in vivo anti-influenza virus activity was observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018983715982
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    Paper (German National Licenses)
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  • 5
    Electronic Resource
    Electronic Resource
    Epimerization Kinetics of Moxalactam in Frozen Solution (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 266-271 
    Details
    ISSN: 1573-904X
    Keywords: moxalactam ; epimerization ; frozen solution ; ice ; activation energy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The epimerization rate constants of R- and S-epimers of moxalactam (LMOX) in a frozen aqueous solution decreased as the temperature decreased. The reaction proceeded in the unfrozen region remaining in the frozen solution, without being affected by the ice. The reaction stopped completely below the collapse temperature of the LMOX aqueous solution. The ratio of R- and S-epimers at equilibrium, which was equal to the ratio of the epimerization rate constant, increased as the temperature decreased. This change in the ratio at equilibrium could be ascribed to the difference in the activation energy between the two epimers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015918518922
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  • 6
    Electronic Resource
    Electronic Resource
    Epimerization Kinetics of Moxalactam in Frozen Urine and Plasma Samples (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 364-369 
    Details
    ISSN: 1573-904X
    Keywords: moxalactam ; epimerization ; frozen plasma ; frozen urine ; electrolyte ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The epimerization of moxalactam (LMOX) in frozen urine and plasma samples was studied during long-term storage. The R/S ratio at equilibrium [(R/S)eq] at −10°C was similar in urine and in rat and human plasma ultrafiltrate but differed from that in water. The (R/S)eq values in human plasma and its ultrafiltrate differed slightly, while they were the same in rat plasma and in its ultrafiltrate. The difference for the human plasma and ultrafiltrate may result from differences in plasma protein binding between R- and S-epimers in the liquid region of the frozen plasma. The change of R/S ratio in frozen human plasma continued below the collapse temperature of LMOX aqueous solution, where the liquid region appeared still to exist as determined by NMR measurement. Consequently, the biological LMOX samples should be preserved at or below −70°C to prevent changes in the R/S ratio.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015815321570
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    Paper (German National Licenses)
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