Pathways of gallopamil metabolism. Regiochemistry and enantioselectivity of the O-demethylation processes.
The oxidative O-demethylation of pseudoracemic gallopamil by rat and human liver microsomes was studied. By comparison of GC/MS retention times and fragmentation patterns with data from authentic standards, the four possible regioisomeric monophenolic metabolites, 2-(4-hydroxy-3,5-dimethoxyphenyl)-2-isopropyl-5-[(3,4- dimethoxyphenethyl)methylamino]-valeronitrile (2), 2-(5-hydroxy-3,4-dimethoxyphenyl)-2-isopropyl-5-[(3,4- dimethoxyphenethyl)methylamino]valeronitrile (3), 2-(3,4,5-trimethoxyphenyl)-2-isopropyl-5-[(4-hydroxy-3-methoxyphenethyl) -methylamino]valeronitrile (4), and 2-(3,4,5-trimethoxyphenyl)-2-isopropyl-5-[(3-hydroxy-4- methoxyphenethyl)methylamino]valeronitrile (5), were characterized. Rat liver microsomal oxidation produced all four regioisomeric monophenols which accounted for only 10% of the oxidative metabolism, the remaining 90% being N-dealkylation metabolites. Preference for metabolism of the O-methyl ethers at p-positions on each of the aromatic ring systems was noted, with more O-demethylation of the O-methyl ethers on the aromatic ring adjacent to the chiral center than on the aromatic ring in the short side chain. Significant enantio-selectivity was noted, the S/R ratios being 2.26, 1.97, 1.87 and 1.30 for formation of 2, 3, 4 and 5, respectively. Biliary excretion of the O-demethylated metabolites as conjugates, cleaved by beta-glucuronidase, was observed in rats after administration of pseudoracemic gallopamil. Significant stereoselectivity was noted, S/R ratios being 0.62, 1.61, 1.49 and 2.19 for 2, 3, 4 and 5, respectively. Human liver microsomal oxidation produced more p- than m-O-demethylation, with 4 less than 5, and 2 less than 3, but quantitatively the pathway is a minor one compared to N-dealkylation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mutlib
A E
AE
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Nelson
W L
WL
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D003640:Dealkylation; D005711:Gallopamil / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005966:Glucuronidase / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism
D005711:Gallopamil; D005966:Glucuronidase