Pharmacodynamic Response of Entacapone in Rats after Administration of Entacapone Formulations and Prodrugs with Varying Bioavailabilities

The aim of this in vivo study was to assess the effect of improved oral bioavailability of entacapone on its actual pharmacodynamic response, COMT inhibition in erythrocytes. Rats were administered entacapone orally as a suspension, as a plain solution, an entacapone/HP‐β‐CD solution, two N‐alkyl‐carbamate ester prodrugs and intravenously as a solution. Also the relationship between pharmacodynamic and pharmacokinetic responses of entacapone was investigated. The administration of entacapone as a solution (plain solution pH 7.4; F=34.8% or entacapone/HP‐β‐CD solution pH 3.0; F=18.5%) resulted in significantly higher degree of COMT inhibition in erythrocytes than could be achieved by administering entacapone as a suspension (pH 3.0; F=8.9%). The inhibitory E max model did not reveal any significant differences in EC 50 estimates of entacapone suspension, entacapone/HP‐β‐CD solution or entacapone solution. The overall pharmacodynamic response of entacapone (AUE; area under effect‐time curve) was dependent on the pharmacokinetic response (AUC; area under concentration‐time curve) irrespective of the entacapone formulation and dosage form. However, this dependency did not extend to formulations producing very high peak concentrations of entacapone in plasma; high plasma concentrations reached transiently after administration of entacapone solution had only a minor effect on the overall pharmacodynamic response (AUE). The inhibitory E max model revealed that a plateau of COMT inhibition near to E max is attained by plasma concentrations under 2000 ng/ml, irrespective of the formulation. This supports the results concerning the dependence of AUE on AUC.