Relationship between pharmacokinetics and pharmacodynamics of XXXX and its metabolites in @entity1 .

@entity1 @entity38568 @entity17728
The pharmacokinetic properties and hemodynamic effect of @entity17728 and its pharmacologically active metabolite @entity38568 were investigated in 13 healthy volunteers following single oral doses. Hemodynamic changes were measured by finger plethysmography (peripheral arterial resistance), impedance plethysmography (venous distensibility), heart rate, and blood pressure. Plasma concentrations of @entity17728 , @entity38568 , and SIN-1C were measured by means of high-pressure liquid chromatography. Oral administration of rapidly dissolving tablets of @entity17728 (2 tablets of 4 mg), a sustained-release form of @entity17728 (8 mg), and @entity38568 (4 mg) caused an increase of the a/b ratio of the finger plethysmogram and an increase of the venous distensibility. Heart rate and blood pressure remained unaffected. The time course of the peripheral arterial effect mimicked the time course of plasma concentrations of @entity17728 and @entity38568 . Similar to the results in animals, @entity17728 was metabolized in @entity1 to @entity38568 and subsequently degraded to the inactive metabolite SIN-1C. The kinetic profile of both metabolites could be followed in the plasma. The rate-limiting step in the metabolic sequence of @entity17728 was found to be enzymatic hydrolysis and decarboxylation of @entity17728 to @entity38568 . Concentration-response curves of the a/b ratio of the finger plethysmogram showed that the plasma concentrations required to produce a definite effect are much higher for @entity17728 than for @entity38568 . This shows that the pharmacodynamically active form of @entity17728 in @entity1 is the metabolite @entity38568 . The changes in the finger plethysmogram produced by @entity38568 suggest that in addition to the effect on the venous site, @entity38568 also dilates the peripheral arterial site.
