Nonlinear dorzolamide pharmacokinetics in rats: concentration-dependent erythrocyte distribution and drug-metabolite...

The disposition of dorzolamide, a carbonic anhydrase-II (CA-II) inhibitor, was examined in rats after oral and iv administration of 0.05, 0.5, 5, and 25 mg/kg. The area under the blood concentration-time curve (AUC) increased in an approximately dose-proportional fashion up to 0.5 mg/kg. However, at the higher dorzolamide doses there was an unusual 52% decrease in AUC with increasing dose from 0.5 to 25 mg/kg. This was due to a combination of concentration-dependent red blood cell (RBC)/plasma distribution and a competitive drug-metabolite displacement interaction that increased the time-averaged blood clearance by more than 100-fold over the dose range examined. Extensive and saturable binding to the CA-II that is present in RBCs is characteristic of this compound class. However, saturation of binding to the blood enzyme was not sufficient to explain the observed decrease in the AUC at the higher dose levels. A further increase in blood clearance was attributed to the displacement of dorzolamide from the CA-II binding sites by its active N-desethyl metabolite. The proposed mechanism was evaluated in studies that examined the effect of the metabolite on the distribution of dorzolamide between RBCs and plasma. Ex vivo and in vitro assessments of the equilibrium RBC/ plasma concentration ratio indicated that metabolite displacement of dorzolamide from enzyme binding sites in RBC occurs at pharmacologically relevant concentrations.