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.