Stereoselective metabolism of fenoldopam and its metabolites in human liver microsomes, cytosol, and slices.

Abstract

Fenoldopam is a racemic mixture (R-FEN, S-FEN) that is a selective dopamine (DA-1) receptor agonist with pronounced cardiovascular and renal effects in humans. Metabolism of fenoldopam in human liver microsomes, cytosol, and slices was stereoselective for glucuronidation, sulfation, and methylation. Microsomal and cytosolic fractions were supplemented with appropriate cofactors to obtain enzyme activity. There was no evidence of metabolism of fenoldopam by cytochrome P-450. R-FEN was metabolized to fenoldopam-8-sulfate (8-SO4), 7-methoxy fenoldopam (7-MeO), 8-methoxy fenoldopam (8-MeO), and two glucuronidated products. The 7-MeO formed with incubation of R-FEN in human liver slices was further metabolized to an unknown sulfated product. S-FEN was metabolized to fenoldopam-7-sulfate (7-SO4), a second unknown sulfated product, 7-MeO, 8-MeO, and two glucuronidated products. Metabolism of S-FEN and R-FEN in human liver slices to 7-MeO occurred at the same rate, whereas further metabolism of 7-MeO was stereospecific and slower for the S-isomer of 7-MeO. Fenoldopam has served as an excellent model compound for comparison of metabolism in human liver slices with metabolism in subcellular fractions. The parallel pathways of fenoldopam metabolism lessen the possible impact of drug-drug interactions.