Uptake of rosuvastatin by isolated rat hepatocytes: Comparison with pravastatin

K. Nezasa, Kazutaka Higaki, M. Takeuchi, M. Nakano, M. Koike

Research output: Contribution to journalArticle

75 Citations (Scopus)

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 (Km) of uptake rate for rosuvastatin (9.17 μM) was approximately half that for pravastatin (16.5 μM). However, the maximum uptake rate (Vmax) and carrier-mediated uptake clearance (Vmax/Km) 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 (Ki) (2.75 μM) relatively similar to its Km. 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.

Original languageEnglish
Pages (from-to)379-388
Number of pages10
JournalXenobiotica
Volume33
Issue number4
Publication statusPublished - Apr 1 2003

Fingerprint

Pravastatin
Rats
Hepatocytes
Liver
Adenosine Triphosphate
Organic Anion Transporters
Pharmaceutical Preparations
Sulfobromophthalein
Active Biological Transport

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Nezasa, K., Higaki, K., Takeuchi, M., Nakano, M., & Koike, M. (2003). Uptake of rosuvastatin by isolated rat hepatocytes: Comparison with pravastatin. Xenobiotica, 33(4), 379-388.

Uptake of rosuvastatin by isolated rat hepatocytes : Comparison with pravastatin. / Nezasa, K.; Higaki, Kazutaka; Takeuchi, M.; Nakano, M.; Koike, M.

In: Xenobiotica, Vol. 33, No. 4, 01.04.2003, p. 379-388.

Research output: Contribution to journalArticle

Nezasa, K, Higaki, K, Takeuchi, M, Nakano, M & Koike, M 2003, 'Uptake of rosuvastatin by isolated rat hepatocytes: Comparison with pravastatin', Xenobiotica, vol. 33, no. 4, pp. 379-388.
Nezasa K, Higaki K, Takeuchi M, Nakano M, Koike M. Uptake of rosuvastatin by isolated rat hepatocytes: Comparison with pravastatin. Xenobiotica. 2003 Apr 1;33(4):379-388.
Nezasa, K. ; Higaki, Kazutaka ; Takeuchi, M. ; Nakano, M. ; Koike, M. / Uptake of rosuvastatin by isolated rat hepatocytes : Comparison with pravastatin. In: Xenobiotica. 2003 ; Vol. 33, No. 4. pp. 379-388.
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