J. Dow et al., NOVEL CARBAMATE METABOLITES OF MOFEGILINE, A PRIMARY AMINE MONOAMINE-OXIDASE-B INHIBITOR, IN DOGS AND HUMANS, Drug metabolism and disposition, 22(5), 1994, pp. 738-749
Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene b
utanamine hydrochloride) is a selective enzyme-activated irreversible
inhibitor of monoamine oxidase B, which is under development for use i
n the treatment of Parkinson's disease. Male beagle dogs were given si
ngle po (20 mg/kg) and iv (5 mg/kg) doses of [C-14]-Mofegiline. Total
radioactivity excreted in urine and feces over 96 hr was, respectively
, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after po and 67.9 +/- 0.5
and 3.9 +/- 2.4% after iv administration. Unchanged drug in urine repr
esented 3% of the dose after po and less than 1% after iv administrati
on. Mofegiline was thus extensively metabolized in dogs, and urinary e
xcretion was the major route of elimination of metabolites. HPLC, with
on-line radioactivity detection, showed the presence of four major pe
aks (M(1), M(2), M(3), and M(4)), representing respectively 50, 9, 5,
and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS
, FAB MS, and NMR spectra of the purified metabolites were obtained. M
(1), the major metabolite in dogs, was shown to have undergone defluor
ination of the beta-fluoromethylene moiety, and one carbon addition. I
ts structure was confirmed to be a cyclic carbamate. M(2) was a N-carb
amoyl O-beta-D-glucuronide conjugate of parent drug. The formation of
M(1) and M(2) is likely to involve initial reversible addition of CO2
to the primary amine function. M(3) was a N-succinyl conjugate of the
parent drug. M(4) had also undergone defluorination to yield a urea ad
duct of an unsaturated alpha, beta aldehyde. Structures of M(1) end M(
3) were further confirmed by comparing their MS and NMR spectra with t
hose of authentic reference compounds. TSP-LC-MS ion chromatograms of
human urine, obtained from two male volunteers after po administration
of 24 mg of drug, showed selected molecular ion peaks with the same r
etention time as the metabolites identified in dogs. In humans, these
common metabolites represented a similar percentage of the administere
d dose to that in dogs. The present study demonstrates that NMR, TSP-L
C-MS, and FAR-MS are complementary analytical techniques, which allow
structural identification of unhydrolyzed drug conjugates. The formati
on of carbamates of amine-containing drugs may be more common than pre
viously reported.