Metabolic Fate of Simvastatin, an Inhibitor of HMG-CoA Reductase (1) : Absorption, Distribution, Metabolism and Excretion of [¹⁴C] Simvastatin after Single Administration in Male Rats

Abstract

Simvastatin is a lactone prodrug whose hydroxy acid (SVA) is a potent competitive inhibitor of HMG-CoA reductase. Disposition and metabolism of the drug were investigated in male rats after administration of [¹⁴C] simvastatin.
1. After oral dosing of [¹⁴C] simvastatin at doses of 3, 10 and 30mg/kg, plasma radioactivity increased proportionally to administered dose with peak plasma concentration at 2hr and declined with half-lives of 3.8 ?? 5.2hr.
2. Radioactivity was rapidly and widely distributed to tissues, reaching maximum levels at 2hr in many of the tissues. The radioactivity was high in the gastrointestinal tract and liver, secondary in the kidney. At 96hr, the level in each tissue was very low when compared with the maximum value. Similar distribution characteristics were observed by whole body autoradiography.
3. Excretion of radioactivity was 8.1% and 83.3% of the dose in urine and feces, respectively, within 96hr after oral administration. In bile-duct cannulated rats, radioactivity excreted into bile and urine represented 45.3% and 3.9% of the dose, respectively. Gastrointestinal absorption of radioactivity was estimated to be about 50% During the enterohepatic circulation study, 31% of the radioactivity excreted in bile was reabsorbed.
4. Hydroxy acid of simvastatin(SVA) was highly bound to serum protein(>90%). After oral administration, the extent of binding of radioactivity to rat plasma protein was 33 ?? 37 %, and red-blood cells to plasma concentration ratio was 0.34 ?? 0.53.
5. Simvastatin was extensively metabolized in rats after oral dosing, and systemic bioavailability estimated on the basis of HMG-CoA reductase inhibitor equivalents was 4%.
6. Plasma radioactivity was comprised mainly of 2, 2-dimethylbutyric acid (DMB), 2, 2-dimethyl-3-hydroxybutyric acid (DMHB) and SVA. In the liver, SVA was the main metabolite. In bile, 3'-hydroxy metabolite of SVA, 6'-caboxylic acid of SVA and a number of unknown metabolites were present. DMHB, DMB glucuronide and the glycine conjugate of DMB were the three major species found in the urine. Simvastatin was difficult to detect in the tissues and excreta examined.