The effect of elevated α₁-acid glycoprotein on the pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, in rats

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 α-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.

Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment

“…Non-clinical data from rats suggest that plasma AGP levels can affect the pharmacokinetics of imarikiren. When imarikiren was administered to rats whose AGP levels were 10 and 27 times higher than control rats, the AUC and C max of total imarikiren increased to 11 and 35 times and 12 and 23 times higher than those in the control rats, respectively [7]. Consistent with these observations, in the current study, AGP levels and exposure of total imarikiren increased with RI, whereas the unbound fraction of imarikiren decreased.…”

“…In vitro plasma protein binding of imarikiren in mice, rats, monkeys, and humans decreased in proportion to plasma imarikiren concentration in all species [6]. An analysis of imarikiren using a variety of protein solutions indicated that imarikiren may mainly bind to α 1 -acid glycoprotein (AGP) in human plasma [7]. In an in vivo study, while imarikiren and M-I were detected in the urine and feces of rats and monkeys and in the bile of rats, the excretion of imarikiren as unchanged drug in urine and bile was low [6].…”

Into the Labyrinth of the Lipocalin α1-Acid Glycoprotein

“…Examples of recent studies on drugs bound by AGP include: Warfarin ( Hanada, 2017 ), Pinometostat ( Smith et al, 2017 ), Aripiprazole ( Nishi et al, 2019 ), Imatinib ( Mic et al, 2020 ), Voriconazole ( Yuan et al, 2020 ), ONO-2160 ( Kono et al, 2019 , 2021 ), SCO-272 ( Ebihara et al, 2018 , 2019 ), and Brigatinib ( Wang et al, 2020 ).…”

Correlation between synthesis of α2-macroglobulin as acute phase protein and degree of hepatopathy in rats

“…All values are expressed as means ± SEM. Area under the concentration-time curve (AUC) for α2M was calculated according to the trapezoidal rule [21,22]. Variations in serum concentrations of α2M, AST, ALT and TP were assessed using unpaired Student's t-test.…”