Metabolic Fate of Simvastatin, an Inhibitor of HMG-CoA Reductase (2) : Absorption, Distribution and Excretion after Consecutive Oral Administration, and Foeto-placental Transfer and Excretion into Milk of [¹⁴C] Simvastatin in Rats

Abstract

Absorption, distribution and excretion of [¹⁴C] simvastatin were studied in male rats after 21-day consecutive daily oral administration at the dose of 10 mg/kg.
Plasma levels of [¹⁴C] simvastatin at 1hr after each administration did not increase during and after repeated administration. The radioactivity levels-time curve after the final administration was similar to that after the first dosing.
The cumulative excretion of radioactivity in urine and feces accounted for 9.0% and 91.4% of the total dose, respectively, within 96hr after the final administration.
After the final administration, radioactivity was concentrated in the gastrointestinal tracts, liver and kidney. The distribution pattern was similar to that observed after the single administration. There was no accumulation of the drug and its metabolites in the tissues of rats after the consecutive oral administration of [¹⁴C] simvastatin.
Foeto-placental transfer and excretion of radioactivity into milk were studied in pregnant and lactating rats after single oral administration of [¹⁴C] simvastatin.
Whole body autoradiograms of rats on day 12 and 18 of gestation showed low distribution and rapid elimination of radioactivity from the fetus. On day 18 of gestation, the concentration of radioactivity in the placenta, amniotic fluid and fetal tissues were nearly equal to or less than those in the maternal plasma. The amount of radioactivity transferred into a fetus was about 0.02% of the oral dose.
The concentrations of radioactivity in the milk were about 20-54% of those in maternal plasma.