The effect of elevated α 1-acid glycoprotein on the pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, in rats

Xenobiotica. 2019 May;49(5):584-590. doi: 10.1080/00498254.2018.1480817. Epub 2018 Jun 25.

Abstract

The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma α1-acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes. TAK-272 has been shown to primarily bind to AGP in the human plasma. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels.

Keywords: Pharmacokinetics; TAK-272; plasma protein binding; α-acid glycoprotein.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzimidazoles / adverse effects
  • Benzimidazoles / pharmacokinetics*
  • Benzimidazoles / pharmacology*
  • Male
  • Morpholines / adverse effects
  • Morpholines / pharmacokinetics*
  • Morpholines / pharmacology*
  • Orosomucoid / metabolism*
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Renin / antagonists & inhibitors*
  • Turpentine / pharmacokinetics
  • Turpentine / pharmacology

Substances

  • Benzimidazoles
  • Morpholines
  • Orosomucoid
  • Piperidines
  • imarikiren hydrochloride
  • Renin
  • Turpentine