A Retrospective Analysis of Fenoldopam Renal Excretion in 65 Subjects: Evidence for Possible Intrarenal Formation of Fenoldopam from Its Metabolites

Abstract

Clinical studies have suggested that the dopamine DA₁ agonist, fenoldopam, may exhibit nonlinear renal excretion in humans. A retrospective population pharmacokinetic analysis of the renal excretion of fenoldopam and one of its major metabolites, fenoldopam-8-sulfate, was conducted in 65 healthy volunteers to examine this phenomenon. Fenoldopam-8-sulfate exhibited a mean (±SE) renal plasma clearance of 129 ± 4 ml/min, which was independent of its AUC. In contrast, fenoldopam renal plasma clearance ranged from 2220 to 150 ml/min and decreased nonlinearily with increasing fenoldopam AUC. Fenoldopam renal clearance was characterized as a function of fenoldopam AUC using a nonlinear saturation model. The analysis predicted an initial maximal renal clearance of 2852 ml/min, which decreased to 78 ml/min at maximal inhibition. The fenoldopam AUC required to half-saturate fenoldopam renal clearance was 5.2 ng × hr/ml. The elevated clearance values for fenoldopam, beyond normal physiologic limits for renal blood flow in man, suggest that intrarenal formation of fenoldopam from one or more of its circulating metabolites may be contributing to the observed nonlinear decreases in fenoldopam renal excretion. Preliminary data from our laboratory suggest that in vivo desulfation of fenoldopam-8-sulfate to fenoldopam does occur in the dog.