Pharmacokinetics of TAK-475, a Squalene Synthase Inhibitor, in Rats and Dogs

The pharmacokinetics of TAK-475 (lapaquistat acetate), a squalene synthase inhibitor, was investigated in rats and dogs. After oral administration of (14)C-labeled TAK-475 ([(14)C]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 [(14)C]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 [(14)C]TAK-475 to rats. The main elimination route of the radioactivity was fecal excretion after oral administration of [(14)C]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.