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Drug Res (Stuttg). 2013 Jun;63(6):293-9. doi: 10.1055/s-0033-1337927. Epub 2013 Apr 12.

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.

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Drug Metabolism and Pharmacokinetics Research Laboratory, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan.


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.

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