Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs.

Abstract

High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.

• Authors: Tomoyuki Nishimoto, Eiichiro Ishikawa, Hisashi Anayama, Hitomi Hamajyo, Hirofumi Nagai, Masao Hirakata, Ryuichi Tozawa
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 223 Issue 1 Pg. 39-45 (Aug 15 2007) ISSN: 0041-008X [Print] United States
• PMID: 17599378 (Publication Type: Journal Article)

Chemical References

• 1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid
• Biomarkers
• Enzyme Inhibitors
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Oxazepines
• Piperidines
• Pyridines
• mevalonolactone
• Cholesterol
• cerivastatin
• Farnesyl-Diphosphate Farnesyltransferase
• Creatine Kinase
• Mevalonic Acid

Topics

• Animals
• Biomarkers (metabolism)
• Cholesterol (blood)
• Creatine Kinase (metabolism)
• Drug Antagonism
• Drug Therapy, Combination
• Enzyme Inhibitors (pharmacology)
• Farnesyl-Diphosphate Farnesyltransferase (antagonists & inhibitors)
• Guinea Pigs
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects)
• Male
• Mevalonic Acid (analogs & derivatives, pharmacology)
• Muscle, Skeletal (drug effects, enzymology, pathology)
• Muscular Diseases (chemically induced, pathology, prevention & control)
• Oxazepines (pharmacology)
• Piperidines (pharmacology)
• Pyridines (adverse effects)