Evaluation of myopathy risk for HMG-CoA reductase inhibitors by urethane infusion method.

Abstract

Purpose of the present study was to evaluate the myopathy risk using a urethane infusion method following oral administration of five kinds of commercial HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (HCRIs), (pravastatin (PV), simvastatin (SV), cerivastatin (CeV), atorvastatin (AV), and fluvastatin (FV)) alone or with coadministration of bezafibrate (BF). The solubility of HCRIs in various solvents was determined as a criterion of the physicochemical property. The plasma creatine phosphokinase (CPK) level as a marker of myopathy in normal rats was screened under urethane infusion after oral administration of HCRI alone or with BF coadministration. Also, renal tissue specimens were prepared and the myoglobin remaining in the tissue was visualized by the labeled avidin-biotin technique. The plasma CPK level in normal rats under urethane infusion following oral administration of five kinds of HCRI increased as the dose of HCRI increased, and coadministration of BF further increased the CPK level for each drug. The risk of myopathy evaluated from the CPK level was ranked as follows: CeV>FV>AV>SV>PV. Myoglobin deposition was observed in the cast of proximal tubules, cytoplasm of distal tubules and collecting ducts of rat kidney extracted from rats treated with HCRIs under urethane infusion. Histopathological findings showed that the extent of myoglobin deposition increased on coadministration of BF with each drug. The correlation was found for myopathy risk evaluated by CPK level using the urethane infusion method and drug lipophilicity, ie., the water/n-octanol partition coefficient except for the case of SV. Histopathological findings for the kidney following HCRI treatment also reflected the CPK level in rats under urethane infusion.