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.

Key words

pharmacokinetics - ADME - concentration-dependent - erythrocyte distribution

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