Effect of medium pH on the cytotoxicity of hydrophilic statins.
OBJECTIVE
The aim of this study was to examine the mechanism of pravastatin- and rosuvastatin-induced cytotoxicity and the relationship between pravastatin- and rosuvastatin-induced cytotoxicity and medium pH using human prototypic embryonal rhabdomyosarcoma cell line (RD) and rat myoblast cell line (L6) as a model of in vitro skeletal muscle.


METHODS
Statin-induced reduction of cell viability and apoptosis was measured by 3-(4,5-dimethylthiazol-2-yl)2,5 -diphenyl tetrazolium bromide (MTT) assay and caspase assay. Intracellular accumulation of statins was determined using an HPLC system.


RESULTS
Rosuvastatin cytotoxicity, reduction of cell viability, morphological changes and caspase activation at acidic pH (pH 6.8) were significantly greater than those at neutral pH (pH 7.4). Rosuvastatin accumulation at acidic pH was greater than that at pH 7.4. On the other hand, medium pH had no effect on pravastatin accumulation.


CONCLUSIONS
Rosuvastatin cytotoxicity at acidic pH is associated with increasing intracellular accumulation of rosuvastatin. On the other hand, medium pH had no effect on cytotoxicity of pravastatin.
Kobayashi
Masaki
M
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
Kagawa
Toshiki
T
Takano
Rumi
R
Itagaki
Shirou
S
Hirano
Takeshi
T
Iseki
Ken
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005464:Fluorobenzenes / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032446:Myoblasts; D017035:Pravastatin / Q000493:pharmacokinetics / Q000633:toxicity*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D018233:Rhabdomyosarcoma, Embryonal; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000633:toxicity*; D013778:Tetrazolium Salts; D013844:Thiazoles; D018675:Toxicity Tests
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013778:Tetrazolium Salts; D013844:Thiazoles; D000068718:Rosuvastatin Calcium; D020169:Caspases; C022616:thiazolyl blue; D017035:Pravastatin