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Uptake of rosuvastatin by isolated rat hepatocytes: comparison with pravastatin.
- Source :
-
Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2003 Apr; Vol. 33 (4), pp. 379-88. - Publication Year :
- 2003
-
Abstract
- 1. The liver is the target organ for the lipid-regulating effect of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and liver-selective uptake of this drug is therefore a desirable property. The uptake kinetics of rosuvastatin were investigated and compared with those of pravastatin using isolated rat hepatocytes. 2. Uptake for both drugs involved both active transport and passive diffusion processes. The Michaelis constant (K(m)) of uptake rate for rosuvastatin (9.17 micro M) was approximately half that for pravastatin (16.5 micro M). However, the maximum uptake rate (V(max)) and carrier-mediated uptake clearance (V(max)/K(m)) of rosuvastatin were significantly (p < 0.01) greater than those of pravastatin, and a larger contribution of carrier-mediated uptake clearance to total uptake clearance was shown for rosuvastatin (contribution ratio 0.903 versus pravastatin 0.654). 3. Sodium and chloride ions did not play a significant role in the uptake of rosuvastatin and pravastatin, but the uptake of both drugs was inhibited both by depletion of cellular ATP and by organic anions such as bromosulfophthalein. 4. Rosuvastatin competitively inhibited the uptake of pravastatin, with an inhibition constant (K(i)) (2.75 micro M) relatively similar to its K(m). 5. The results suggest that an organic anion transport protein is the main mediator of the hepatic uptake of rosuvastatin and pravastatin, which occurs in an ATP-dependent manner. Our results indicated that rosuvastatin was taken up by the hepatocytes via the same transport systems as pravastatin, but with a greater affinity and efficiency than pravastatin.
- Subjects :
- Algorithms
Animals
Anion Transport Proteins metabolism
Anticholesteremic Agents pharmacokinetics
Antimetabolites pharmacology
Binding, Competitive drug effects
Diffusion
Fluorobenzenes pharmacokinetics
Hepatocytes drug effects
Kinetics
Male
Pravastatin pharmacokinetics
Proteins metabolism
Pyrimidines pharmacokinetics
Rats
Rats, Sprague-Dawley
Rosuvastatin Calcium
Sulfonamides pharmacokinetics
Anticholesteremic Agents metabolism
Fluorobenzenes metabolism
Hepatocytes metabolism
Pravastatin metabolism
Pyrimidines metabolism
Sulfonamides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0049-8254
- Volume :
- 33
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Xenobiotica; the fate of foreign compounds in biological systems
- Publication Type :
- Academic Journal
- Accession number :
- 12745873
- Full Text :
- https://doi.org/10.1080/0049825031000066259