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

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

• References

• 1 Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007; 49: 2231-2237
• 2 Marcuzzi 1 A, Zanin V, Kleiner G et al. Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients. Pediatr Res 2013; 74: 266-271
• 3 Schneiders MS, Houten SM, Turkenburg M et al. Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency. Arthritis Rheum 2006; 54: 2306-2313
• 4 Miki T, Kori M, Mabuchi H et al. Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis. J Med Chem 2002; 45: 4571-4580
• 5 Nishimoto T, Amano Y, Tozawa R et al. Lipid-lowering property of TAK-475, a squalene synthase inhibitor, in vivo and in vitro. Br J Pharmacol 2003; 139: 911-918
• 6 Amano Y, Nishimoto T, Tozawa R et al. Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia. Eur J Pharmacol 2003; 466: 155-161
• 7 Karim A, Abeyratne A, Siebert F et al. TAK-475, a squalene synthase inhibitor: Mass balance and excretion study. Clinical Pharmacology & Therapeutics 2007; 81 (Suppl. 01) S114
• 8 Taketani M, Shii M, Ohura K et al. Carboxylesterase in the liver and small intestine of experimental animals and human. Life Sci 2007; 81: 924-932
• 9 Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 2006; 27: 425-446 Review