Characterization of the hemodynamic activities of fenoldopam and its enantiomers in the dog

Abstract

Fenoldopam (SK&F 82526) is a potent and selective dopamine DA-1 agonist with demonstrated renal vasodilator and antihypertensive activities in experimental animals and humans. Fenoldopam is a racemic mixture of two enantiomers, SK&F R-82526 and SK&F S-82526. The R-enantiomer is uniformly reported to be more potent than the racemate; in contrast, there is controversy regarding potency of the S-enantiomer. In these studies, the renal and systemic hemodynamic activities of fenoldopam and its enantiomers are characterized in anesthetized, phenoxybenzamine-treated dogs. The results show that the renal and systemic vasodilator activities of fenoldopam are properties of the R-enantiomer; the S-enantiomer is essentially inactive. The renal and systemic vasodilator properties of SK&F R-82526 are antagonized in a competitive fashion by the DA-1 antagonist, SK&F R-83566, but not the DA-2 antagonist, domperidone. Ganglionic blockade did not attenuate renal vasodilation associated with SK&F R-82526. Thus, the mechanism of SK&F R-82526-associated vasodilation, like that previously established for fenoldopam, is via stimulation of postganglionic DA-1 receptors.

Preliminary pharmacokinetics and cardiovascular effects of fenoldopam continuous rate infusion in six healthy dogs

“…This study aimed to look at both clearance and elimination of fenoldopam, without distinguishing enantiomers or major metabolites. It has been shown in dogs that the renal and systemic vasodilator activities of fenoldopam are properties of the R‐enantiomer and that the S‐enantiomer is essentially inactive (Kinter et al. , 1990).…”

“…This study aimed to look at both clearance and elimination of fenoldopam, without distinguishing enantiomers or major metabolites. It has been shown in dogs that the renal and systemic vasodilator activities of fenoldopam are properties of the R-enantiomer and that the S-enantiomer is essentially inactive (Kinter et al, 1990). Consequently, it is possible that if there is differential elimination of the enantiomers, the measured fenoldopam (combined R-and S-form) concentrations may not reflect the active drug level.…”

Effect of fenoldopam on renal function after nephrotomy in normal dogs

“…Dopamine receptors first identified in the central nervous system were classified as D1 and D2. There are at least 2 subtypes of peripheral dopamine receptors: DA‐1 found in vascular smooth muscle and DA‐2 found in sympathetic nerve endings 4‐7 . Differential receptor activation explains the distinct cardiovascular and renal responses observed with various doses of dopamine.…”

“…There are at least 2 subtypes of peripheral dopamine receptors: DA-1 found in vascular smooth muscle and DA-2 found in sympathetic nerve endings. [4][5][6][7] Differential receptor activation explains the distinct cardiovascular and renal responses observed with various doses of dopamine. Dopaminergic effects generally predominate, but, at higher doses, adrenoceptors are activated, which may result in tachyarrhythmias, hypotension, myocardial or splanchnic ischemia, systemic vasoconstriction, or reduced GFR.…”

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

“…Fenoldopam is a racemic mixture of two enantiomers, SK&F R-82526 and SK&F S-82526. The results showed that the renal and systemic vasodilator activities of fenoldopam are properties of the Renantiomer via stimulation of postganglionic DA-1 receptors; the S-enantiomer is essentially inactive [64]. Ingenol mebutate (Picato) by Leo Pharma was approved in 2012 by FDA for treatment of actinic keratosis.…”