Abstract
The pharmacokinetics of TAK-475 (lapaquistat acetate), a squalene synthase inhibitor,
was investigated in rats and dogs. After oral administration of 14C-labeled TAK-475 ([14C]TAK-475) to rats and dogs at a dose of 10 mg/kg, the bioavailability (BA) was relatively
low at 3.5 and 8.2%, respectively. The main component of the radioactivity in the
plasma was M-I, which has a comparable pharmacological activity to TAK-475 in vitro.
The radioactivity in the portal plasma after intraduodenal administration of [14C]TAK-475 to portal vein-cannulated rat was also mainly M-I, suggesting that most
of the TAK-475 was hydrolyzed to M-I during the permeable process in the intestine.
The concentrations of M-I in the liver, the main organ of cholesterol biosynthesis,
were much higher than those in the plasma after oral administration of [14C]TAK-475 to rats. The main elimination route of the radioactivity was fecal excretion
after oral administration of [14C]TAK-475 to rats and dogs, and the absorbed radioactivity was mainly excreted via
the bile as M-I in rats. M-I excreted into the bile was partially subjected to enterohepatic
circulation. These results suggest that although the BA values of TAK-475 are low,
M-I can exert compensatory pharmacological effects in the animals. These pharmacokinetic
characteristics in animals were also confirmed in the clinical studies. The evaluation
of M-I disposition is important for the pharmacokinetics, pharmacodynamics and toxicity
of TAK-475 in animals and humans.
Key words
lapaquistat acetate - ADME - active metabolite
