Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone
| ISSN: |
0005-2736
|
|---|---|
| Keywords: |
(Rat) ; Bile acid ; HMG-CoA reductase inhibitor ; Liver ; Pravastatin ; Transport
|
| Source: |
Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
|
| Topics: |
Biology
Chemistry and Pharmacology
Medicine
Physics
|
| Type of Medium: |
Electronic Resource
|
| URL: |
| _version_ | 1798292199195017216 |
|---|---|
| autor | Ziegler, K. Hummelsiep, S. |
| autorsonst | Ziegler, K. Hummelsiep, S. |
| book_url | http://linkinghub.elsevier.com/retrieve/pii/0005-2736(93)90272-2 |
| datenlieferant | nat_lic_papers |
| fussnote | Pravastatin and pravastatin-lactone are not taken up into extrahepatic cells such as fibroblasts, or hepatoma cells such as AS-30D ascites hepatoma cells or FAO cells. In contrast, pravastatin is taken up into isolated rat hepatocytes by a carrier mediated, saturable, temperature-dependent and energy-dependent mechanism. The kinetic parameters for the saturable uptake are K"m 27 μM, V"m"a"x 537 pmol/mg per min. The permeability coefficients were determined to be 9.829.10-^7 cm/s at 4^oC, 1.76.10-^6 cm/s at 7^oC, 3.85.10-^6 cm/s at 17^oC and if5.82.10-^6 cm/s at 37^oC. The activation energy is 60 KJ/mol for 100 μM pravastatin at 37^oC. The Q"1"0 values are between 1.7 and 2.8. In the presence of metabolic inhibitors and in the absence of oxygen, transport is inhibited. Uptake of pravastatin is not dependent on an extracellular to intracellular sodium-gradient. Replacement of chloride by sulfate, nitrate, gluconate or thiocyanate significantly inhibits the uptake of pravastatin. Uptake is competitively inhibited by cholate and taurocholate in the presence and absence of sodium. Pravastatin, however, competitively inhibits the uptake of cholate and taurocholate only in the absence of sodium. In addition, pravastatin-lactone enters liver cells via an energy-dependent, carrier-mediated uptake system. For the saturable energy-dependent part of the hepatocellular uptake a K"m value of 9 μM and a V"m"a"x value of 621 pmol/mg per min was determined. The permeability coefficient of pravastatin-lactone uptake is calculated to be 5.41.10-^6 cm/s at 37^oC. The uptake of pravastatin-lactone is competitively-noncompetitively inhibited by pravastatin and by lovastatin and vice versa. These results indicate that the hepatoselectivity of pravastatin is due to its carrier-mediated uptake into rat hepatocytes via a sodium-independent bile acid carrier. Pravastatin-lactone resembles pravastatin-sodium in its hepatoselectivity. |
| hauptsatz | hsatz_simple |
| identnr | NLZ185723691 |
| iqvoc_descriptor_keyword | iqvoc_00000124:Transport |
| issn | 0005-2736 |
| journal_name | Biochimica et Biophysica Acta (BBA)/Biomembranes |
| materialart | 1 |
| package_name | Elsevier |
| publikationsort | Amsterdam |
| publisher | Elsevier |
| reference | 1153 (1993), S. 23-33 |
| schlagwort | (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport |
| search_space | articles |
| shingle_author_1 | Ziegler, K. Hummelsiep, S. |
| shingle_author_2 | Ziegler, K. Hummelsiep, S. |
| shingle_author_3 | Ziegler, K. Hummelsiep, S. |
| shingle_author_4 | Ziegler, K. Hummelsiep, S. |
| shingle_catch_all_1 | Ziegler, K. Hummelsiep, S. Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport 0005-2736 00052736 Elsevier |
| shingle_catch_all_2 | Ziegler, K. Hummelsiep, S. Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport 0005-2736 00052736 Elsevier |
| shingle_catch_all_3 | Ziegler, K. Hummelsiep, S. Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport 0005-2736 00052736 Elsevier |
| shingle_catch_all_4 | Ziegler, K. Hummelsiep, S. Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport (Rat) Bile acid HMG-CoA reductase inhibitor Liver Pravastatin Transport 0005-2736 00052736 Elsevier |
| shingle_title_1 | Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone |
| shingle_title_2 | Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone |
| shingle_title_3 | Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone |
| shingle_title_4 | Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone |
| sigel_instance_filter | dkfz geomar wilbert ipn albert fhp |
| source_archive | Elsevier Journal Backfiles on ScienceDirect 1907 - 2002 |
| timestamp | 2024-05-06T08:44:43.620Z |
| titel | Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone |
| titel_suche | Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone Pravastatin and pravastatin-lactone are not taken up into extrahepatic cells such as fibroblasts, or hepatoma cells such as AS-30D ascites hepatoma cells or FAO cells. In contrast, pravastatin is taken up into isolated rat hepatocytes by a carrier mediated, saturable, temperature-dependent and energy-dependent mechanism. The kinetic parameters for the saturable uptake are K"m 27 μM, V"m"a"x 537 pmol/mg per min. The permeability coefficients were determined to be 9.829.10-^7 cm/s at 4^oC, 1.76.10-^6 cm/s at 7^oC, 3.85.10-^6 cm/s at 17^oC and if5.82.10-^6 cm/s at 37^oC. The activation energy is 60 KJ/mol for 100 μM pravastatin at 37^oC. The Q"1"0 values are between 1.7 and 2.8. In the presence of metabolic inhibitors and in the absence of oxygen, transport is inhibited. Uptake of pravastatin is not dependent on an extracellular to intracellular sodium-gradient. Replacement of chloride by sulfate, nitrate, gluconate or thiocyanate significantly inhibits the uptake of pravastatin. Uptake is competitively inhibited by cholate and taurocholate in the presence and absence of sodium. Pravastatin, however, competitively inhibits the uptake of cholate and taurocholate only in the absence of sodium. In addition, pravastatin-lactone enters liver cells via an energy-dependent, carrier-mediated uptake system. For the saturable energy-dependent part of the hepatocellular uptake a K"m value of 9 μM and a V"m"a"x value of 621 pmol/mg per min was determined. The permeability coefficient of pravastatin-lactone uptake is calculated to be 5.41.10-^6 cm/s at 37^oC. The uptake of pravastatin-lactone is competitively-noncompetitively inhibited by pravastatin and by lovastatin and vice versa. These results indicate that the hepatoselectivity of pravastatin is due to its carrier-mediated uptake into rat hepatocytes via a sodium-independent bile acid carrier. Pravastatin-lactone resembles pravastatin-sodium in its hepatoselectivity. |
| topic | W V WW-YZ U |
| uid | nat_lic_papers_NLZ185723691 |