Abstract
To elucidate the efficacy of TA-870 as a dopamine prodrug, plasma concentrations of metabolites after oral administration of TA-870 or dopamine hydrochoride (DA) to dogs were measured by high performance liquid chromatography. The in vitro metabolism of TA-870 in various animals was also studied. Maximum levels of free DA (active from) in dog plasma after dosing of TA-870 (33.5mg, 71μmol/kg) and DA (13.5mg, 71μmol/kg) were 252ng/ml and 29ng/ml, respectively, the maximum level after dosing of TA-870 being about 9 times higher than that of DA. Ethoxycarbonyl and acetylme thionyl groups in TA-870 structure, designed to protect the catechol and amino groups of DA, successfully suppressed the first pass metabolism of oral DA.
Hydrolysis rate of TA-870 by plasma esterase of different animal species was in the order as follows, rat> guinea pig≈rabbit > human > dog. TA-870 was not converted to DA in the presence of dog plasma, however the conver sion took place in the presence of whole blood of the dog. Conversion rate of TA-870 to DA in different rat tissues was in the order as follows, liver> small intestinal well> blood.
