RT Journal Article
SR Electronic
T1 Structural characterization of urinary metabolites of the antiarrhythmic drug encainide in human subjects.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 28
OP 35
VO 18
IS 1
A1 H K Jajoo
A1 R F Mayol
A1 J A LaBudde
A1 I A Blair
YR 1990
UL http://dmd.aspetjournals.org/content/18/1/28.abstract
AB 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.