Disposition of the New Potent Acetylcholinesterase Inhibitor 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidiny]-1-oxopropyl]-1, 2, 5, 6-tetrahydro-4H-pyrrolo [3, 2, 1-ij] quinolin-4-one (TAK-802) in Rats, Dogs and Monkeys

Abstract

The pharmacokinetics of TAK-802, a potential agent of amelioration for voiding dysfunction, were investigated in rats, dogs and monkeys after a single oral administration of 14C-labeled TAK-802. The values of the bioavailability for the compound ranged from 10.2 to 19.9% and the extent of absorption of 14C were higher than the values for the bioavailability in the tested animals. TAK-802 and its related compounds distributed widely in the tissues including the target organ, the urinary bladder, in rats. TAK-802 was highly bound to the plasma proteins and the protein-binding % was independent of the spiked concentrations in all the species tested. Meanwhile, the erythrocyte distribution decreased significantly with the increase in the TAK-802 concentrations. After oral dosing, the dosed 14C was predominantly excreted into the feces of the test animals and the hepato-biliary route mainly contributed to the excretion of 14C in rats. The major components of 14C in the plasma and excreta were unidentified polar metabolites in the test animals. These results indicated that TAK-802 was extensively metabolized by first-pass metabolism during the absorption process and its related metabolites were excreted predominantly into the feces via the bile in the test animals. The concentration-dependent erythrocyte distribution was characterized as the most influential property on the pharmacokinetics of TAK-802. For the clinical safety in the development of TAK-802, the effect of the concentration-dependent erythrocyte distribution on the pharmacokinetics of TAK-802 in animals and humans should be addressed.

The effects of the concentration‐dependent erythrocyte distribution of TAK‐802, a potent acetylcholinesterase inhibitor, on rat pharmacokinetics

“…dosing mainly depended on the concentration‐dependent erythrocyte distribution. In the erythrocyte distribution study using animals and human blood, the biggest concentration dependency of erythrocyte distribution was also confirmed in human at the tested concentration range . In the candidate selection stage, TAK‐802 exhibited high selectivity and potent inhibitory effects on AchE in an in vitro study using human erythrocyte‐derived acetylcholinesterase with an estimated IC 50 value of 1.5 nmol/l .…”

“…The non‐clinical absorption, distribution, metabolism and excretion (ADME) data revealed that TAK‐802 exhibited a marked concentration‐dependency in the erythrocyte distribution in rats, dogs, monkeys and humans. The erythrocyte distribution changed from 77.0% to 11.5% in rats, 69.3% to 27.2% in dogs and 92.3% to 16.9% in monkeys at the tested concentration range of 1–1000 ng/ml . Especially in humans, the erythrocyte distribution changed significantly and ranged from 4.4% to 91.2% at the tested concentrations .…”

“…In the oral ascending dose study in rats, the pharmacokinetic parameters and plasma concentration curves changed with a dose escalation (Figure and Table ). In the preclinical ADME studies using radiolabeled TAK‐802, the dosed TAK‐802 and its related metabolites were considered to be well absorbed after oral administration to rats . These preclinical in vitro ADME studies in rats and humans also revealed that the percentage of the erythrocyte distribution of [ 14 C]TAK‐802 decreased drastically with an increase in the spiked concentration, despite the concentration‐independent ratios of plasma protein binding of TAK‐802 [7].…”

“…The erythrocyte distribution changed from 77.0% to 11.5% in rats, 69.3% to 27.2% in dogs and 92.3% to 16.9% in monkeys at the tested concentration range of 1–1000 ng/ml . Especially in humans, the erythrocyte distribution changed significantly and ranged from 4.4% to 91.2% at the tested concentrations . However, the ratio of the protein binding of TAK‐802 was independent of the spiked concentration in rats, dogs, monkeys and humans .…”

“…Especially in humans, the erythrocyte distribution changed significantly and ranged from 4.4% to 91.2% at the tested concentrations . However, the ratio of the protein binding of TAK‐802 was independent of the spiked concentration in rats, dogs, monkeys and humans . For some compounds, the concentration‐dependency in the distribution processes in the blood, namely, the concentration‐dependent erythrocyte distribution , and the concentration‐dependent protein binding causes nonlinear pharmacokinetics in animals and humans .…”