Correlation between pharmacokinetics and pharmacologic effects of a new imidazole thromboxane synthetase inhibitor

A new imidazole derivative, sodium 4-[alpha-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoat e dihydrate (1; Y-20811), is a potent selective inhibitor of thromboxane (TX) synthetase and a candidate drug for preventing ischemic circulatory disorders. After oral dosing in beagle dogs, 1 persistently inhibited TX production, although the elimination of the drug was relatively rapid from plasma. The amount of drug distributed in platelets was small. However, 1 was eliminated from platelets very slowly (t1/2 = 41-130 h), the rate of elimination being comparable to the turnover rate of platelets. From the in vitro experiments, an obvious positive correlation was noted between the amount of the drug bound with TX synthetase in platelets and the inhibition of TX production. This correlation suggested that the small amount of 1 detected in platelets in vivo was large enough to inhibit TX production. From these observations, 1 is thought to dissociate extremely slowly from the active sites of TX synthetase. Consequently, the duration of the effect was dependent on the turnover of platelets.