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

• Published in: Toxicology and applied pharmacology Vol. 223; no. 1; pp. 39 - 45
• Main Authors: Nishimoto, Tomoyuki, Ishikawa, Eiichiro, Anayama, Hisashi, Hamajyo, Hitomi, Nagai, Hirofumi, Hirakata, Masao, Tozawa, Ryuichi
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15.08.2007; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ACETATES; Animals; Biological and medical sciences; Biomarkers - metabolism; CHOLESTEROL; Cholesterol - blood; COENZYMES; CORONARIES; CREATINE; Creatine Kinase - metabolism; Drug Antagonism; Drug Therapy, Combination; Enzyme Inhibitors - pharmacology; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors; GUINEA PIGS; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; IN VIVO; INHIBITION; Lapaquistat acetate; Male; Medical sciences; Mevalonic Acid - analogs & derivatives; Mevalonic Acid - pharmacology; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Muscular Diseases - chemically induced; Muscular Diseases - pathology; Muscular Diseases - prevention & control; Myotoxicity; Oxazepines - pharmacology; Piperidines - pharmacology; Pyridines - adverse effects; SIDE EFFECTS; SQUALENE; Squalene synthase inhibitor; Statin; TAK-475; TOXICITY; Toxicology; Squalene synthase inhibitor; Statin; Guinea pigs; Lapaquistat acetate; Myotoxicity; TAK-475; Enzyme; Toxicity; Transferases; Rodentia; Statin derivative; Acetate; Farnesyl-diphosphate farnesyltransferase; Prevention; Vertebrata; Mammalia; Guinea pig; Lapaquistat; Animal; Antilipemic agent
• DOI: 10.1016/j.taap.2007.05.005
• ISSN: 0041-008X

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.