Structural characterization of urinary metabolites of the antiarrhythmic drug encainide in human subjects.
Metabolism of the antiarrhythmic drug encainide was studied in human subjects after a single 50-mg oral dose. Encainide labeled on the carbonyl carbon with 14C and at the benzylic (2'-1-ethyl) carbon with 13C was administered to four normal healthy male subjects. A large proportion of the radioactive dose (42%) was excreted in the urine in the first 24 hr. The total urinary excretion was 47.0 +/- 4.6% and total fecal excretion was 38.7 +/- 5.7% over 5 days. The conjugated metabolites excreted in the urine were hydrolyzed with beta-glucuronidase/arylsulfatase, and were isolated and purified by HPLC. Structural characterization was carried out by a combination of fast atom bombardment-mass spectrometry, gas chromatography/electron impact mass spectrometry, and 1H-NMR spectroscopy. Structures of the metabolites were confirmed by co-elution on HPLC with authentic standards when available. Six metabolites of encainide were identified from the hydrolyzed urine together with unchanged drug. In addition to already known metabolites O-demethyl-encainide, 3-methoxy-O-demethyl-encainide, and N,O-di-demethyl-encainide, three new metabolites were identified: N-demethyl-3-methoxy-O-demethyl-encainide, 3-hydroxy-encainide, and O-demethyl-encainide-lactam. These metabolites accounted for greater than 90% of the radioactivity excreted in the urine. Four major routes of metabolism were identified: first, O-demethylation of the aromatic methyl ether; second, formation of methylated catechol derivatives; third, N-demethylation of the piperidyl nitrogen; and fourth, oxidation at carbon alpha to the piperidyl nitrogen. A plausible scheme for the metabolism of encainide in human subjects is proposed.
Jajoo
H K
HK
Department of Chemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
Mayol
R F
RF
LaBudde
J A
JA
Blair
I A
IA
D000813:Anilides / Q000652:urine*; D001192:Arylsulfatases / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D016700:Encainide; D008401:Gas Chromatography-Mass Spectrometry; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008970:Molecular Weight; D013056:Spectrophotometry, Ultraviolet
D000813:Anilides; D001192:Arylsulfatases; D005966:Glucuronidase; D016700:Encainide