[Effects of acidification and alkalinization agents on statins-induced muscle toxicity].
The aim of this study was to determine the effects of α-cyano-4-hydroxycinnamic acid (CHC), a lactate efflux inhibitor, and citrate, an alkaline reagent, on statin-induced muscle injury using a human prototypic embryonal rhabdomyosarcoma cell line (RD) as a model of in vitro skeletal muscle and on statin-induced muscle damage in an in vivo study. Statin-induced reduction of cell viability and apoptosis was measured by the 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay and caspase assay. In an in vivo study, plasma creatine phosphokinase (CPK) level was examined in cerivastatin-treated rats. CHC increased growth inhibition of RD cells induced by cerivastatin, a lipophilic statin, but not these induced by pravastatin, a hydrophilic statin. On the other hand, citrate suppressed cerivastatin-, simvastatin- and atorvastatin-induced reduction of cell viability and caspase activation in RD cells. Moreover, citrate prevented cerivastatin-induced increase in CPK concentration in a concentration-dependent manner. This is first study to evaluate CHC or citrate-induced exacerbation or improvement of statin-induced muscle damage.
Laboratory of Clinical Pharmaceutics and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Masaki
M
Kobayashi
Kazuhiro
K
Hidaka
Ikumi
I
Chisaki
Natsuko
N
Takahashi
Jiro
J
Ogura
Shirou
S
Itagaki
Takeshi
T
Hirano
Hiroaki
H
Yamaguchi
Ken
K
Iseki
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019343:Citric Acid / Q000494:pharmacology*; D003373:Coumaric Acids / Q000494:pharmacology*; D003402:Creatine Kinase / Q000097:blood; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008297:Male; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D011725:Pyridines / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D018233:Rhabdomyosarcoma, Embryonal / Q000201:enzymology / Q000473:pathology
D003373:Coumaric Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D019343:Citric Acid; C086276:cerivastatin; D003402:Creatine Kinase; D020170:Caspase 1