0090-9556/97/2503-0275-0280$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 3
Characterization of the Metabolites of Carbamazepine in Patient
Urine by Liquid Chromatography/Mass Spectrometry
J. L.
Maggs,
M.
Pirmohamed,
N. R.
Kitteringham, and
B. K.
Park
Department of Pharmacology and Therapeutics, University of
Liverpool
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Abstract |
The urinary metabolites of carbamazepine (CBZ) in epileptic
patients receiving long-term drug treatment have been characterized by
LC/MS. CBZ-10,11-epoxide (9.6-15.0 µg/ml),
trans-10,11-dihydrodiol-CBZ (273.0-400.00 µg/ml), and
CBZ (2.4-3.8 µg/ml) were measured by HPLC. The secondary
N-glucuronide of CBZ, four phenolic
O-glucuronides (including those of 2- and 3-OH-CBZ), two
additional OH-CBZ O-glucuronides, and the
N-glucuronide of CBZ-10,11-epoxide constituted the products of either direct conjugation or preliminary monoxygenation. Derivatives of these monoxygenated compounds, which were characterized as O-glucuronides, were represented by dihydroxylated
(catechol) CBZ and its putative O-methyl metabolite and by
10,11-dihydrodiol-CBZ. 10,11-Dihydro-10-OH-CBZ
O-glucuronide, a metabolite thought to be excreted only by
uremic subjects, was not found. More complicated biotransformations of
the 10,11-ene moiety were revealed by two carbinol products of azepine
ring contraction: 9-OH-methyl-10-carbamoyl acridan and an hydroxylated
derivative thereof, which were excreted as O-glucuronides.
No polar sulfur-containing metabolites that might serve as indicators
of reactive intermediate formation were found in human urine.
| |
Introduction |
Early studies
on the urinary metabolites of CBZ1 (fig. 1)
in epileptic patients, which used GC/MS either with or without prior hydrolysis of the conjugated metabolites (1, 2), identified the
secondary amine-linked glucuronide of CBZ, the O-glucuronide of trans-10,11-DHD-CBZ, and isomeric
O-glucuronides of hydroxy (C-2, C-3, and others), dihydroxy,
and hydroxymethoxy CBZ. In addition, several dihydrodiols, other
oxygenated products, and four isomers of methylsulfoxyhydroxy CBZ
the
latter appeared to be trace metaboliteshave been described but not
quantified (2); certain of these are considered to be derived from
arene oxides. However, the principal pathway of CBZ metabolism in
humans involves the formation of the chemically stable 10,11-epoxide
(3) and its hydrolysis to trans-10,11-DHD-CBZ (4, 5). The
O-glucuronide of 10,11-dihydro-10-hydroxy-CBZ has been found
only as a minor product in uremic subjects (6).
We have analyzed the urinary metabolites of CBZ in patients by means of
LC/MS, which allows direct characterization of polar conjugates (7) and
thereby avoids the ambiguities associated with the decomposition of
dibenzapines to acridans during derivatization and/or GC analysis (2).
Mass chromatograms were examined particularly for any polar
sulfur-containing metabolites (i.e. analytes that may have
avoided detection by GC/MS) that might serve as indicators of the
formation (and deactivation via reaction with glutathione) of arene oxide and other reactive intermediates. These species have
been hypothetically implicated in the causation of the toxicities associated with CBZ treatment (8-10).
Materials and Methods
Patients.
The study was approved by the local ethics committee. Two male patients
(30 and 32 years) and one female (36 years) who had received CBZ
monotherapy (1.2 and 1.8 g/day, respectively) for >1 year collected
urine for 24 hr; aliquots were stored at 
20°C. None of the patients
was receiving other drugs known to be either enzyme inducers or enzyme
inhibitors.
Urinary concentrations of CBZ, CBZ-E, and
trans-10,11-DHD-CBZ were determined by HPLC (5).
Materials.
Standards of CBZ and certain of its nonconjugated metabolites were
obtained as described previously (7).
LC/MS.
Positive-ion ESP mass spectra of CBZ and its metabolites in urine were
obtained by interfacing an Ultratechsphere C18 column (25 cm × 0.46 cm i.d., 5 µm; HPLC Technology, Macclesfield, UK) to
a Quattro II triple quadrupole mass spectrometer (Micromass Ltd.,
Altrincham, Cheshire, UK). Configuration of the LC/MS system has been
described elsewhere (7). Aliquots of untreated urine (100 µl) were
eluted with a gradient of methanol (15% for 5 min, 15-20% over 5 min, 20% for 10 min, 20-50% over 20 min) in 1.0% (v/v) aqueous
acetic acid at 1.2 ml/min; the split flow to the LC/MS interface was
~40 µl/min. Interface temperature was 60°C; capillary voltage,
3.8 × 103 V; counter electrode (HV lens) voltage,
0.28 × 103 V; radiofrequency lens voltage, 0.2 V; and
skimmer voltage, 1.9 V. Centroided mass spectra were acquired between
m/z 100-950 over a scan duration of 4.91 sec; the cycle
time was 5.1 sec. Scans within a chromatographic peak were averaged,
and averaged adjacent (background) scans were subtracted from them to
obtain the final spectrum. Fragmentation of analyte ions (protonated
molecules) during full-scanning acquisitions was achieved by increasing
the skimmer cone voltage from 30 to 50 V. Degradation of selected analyte ions was performed by collision with argon (~8 × 10
4 mbar) at energies of 15-20 eV; the daughter spectra
were acquired from m/z 100 at 1 scan/5 sec. SIM (7 channels)
was conducted with a dwell time of 2 sec and an interchannel delay of
20 msec. Areas of peaks in computer reconstructed mass chromatograms
for protonated molecules were determined at a cone voltage of 30 V to
minimize fragmentation. Both photomultipliers were set at 650 V. All
data were processed via MassLynx II software (Micromass
Ltd.).
| |
Results and Discussion |
Unconjugated Metabolites.
CBZ-E (9.6, 13.9, and 15.0 µg/ml) and trans-10,11-DHD-CBZ
(273.0, 400.0, and 382.9 µg/ml, respectively) were the only
unconjugated metabolites of CBZ found in urine by LC/MS; they were
identified by matching their retention times (40.0 min and 36.5 min,
respectively) and mass spectra with those of authentic standards (table
1). Only small quantities of CBZ (2.4, 2.5, and 3.8 µg/ml), identified by retention time (48 min) alone, were eliminated
in urine.
Glucuronides of CBZ and Its Monoxygenated Metabolites.
The N-glucuronide of CBZ (2) yielded an abundant
protonated molecule ([M + 1]+) at m/z 413 (fig. 2; table 2) and underwent class
characteristic fragmentations (7, 11, 12) attributable to the loss of the dehydroglucuronic acid moiety ([M + 1 176]+) and cleavage of the carbamoyl group ([CBZ + 1 NH3]+). More extensive fragmentation
was achieved by CID (fig. 3; table 2).
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Fig. 2.
Q1 mass chromatograms (LC/MS) for the
[M + 1]+ ions of the glucuronide metabolites of CBZ
found in patient urine.
Analysis was performed at a low cone voltage (30 V) to minimize
fragmentation. Numerals in parentheses refer to structures in fig. 10.
Gluc, glucuronide.
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Fig. 3.
CID (LC/MS/MS) spectrum for [M + 1]+ of the N-glucuronide of CBZ in human urine.
Parent ion, m/z 413.
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The Q1 and Q2 mass chromatograms for glucuronides of monoxygenated
metabolites (m/z 429; fig. 2 and fig. 4) each
contained four consecutive peaks (I-IV) that by virtue of yielding
only the protonated aglycone (m/z 253) upon cone-voltage
fragmentation (table 2) and CID (fig. 5), respectively,
were identified as the four possible phenolic glucuronides
(5). Four OH-CBZ O-glucuronides found in patient
urine during an earlier study were characterized as their permethylated
derivatives, but the positions of functionalization could not be
determined (1). Two chromatographically distinct monoxygenated
glucuronides (VI and VII, RT = 37 and 37.5 min)
and their aglycone fragments were more clearly observed in the Q2 mass
chromatograms (fig. 4). In common with metabolites I-IV, they yielded
only the protonated aglycone when subjected to CID (fig. 5). By process
of elimination, they are taken to be the diastereoisomeric
O-glucuronides of 10-OH-CBZ, conjugates previously
characterized as biotransformation products of 10,11-dihydro-10-oxo-CBZ
(oxcarbazepine) in human urine (12, 13). The fifth and most intense
peak in the Q1 mass chromatogram for m/z 429 corresponded to
the N-glucuronide of CBZ-E (3). It coeluted with
the CBZ-E glucuronide found in the urine of rats administered CBZ-E (7)
and yielded diagnostic fragments (table 2; fig. 4 and fig.
6). CBZ-E glucuronide was not identified in a study that
depended on derivatization before GC/MS (1). It was not possible to
assign the positions of functionalization (C-1 to C-4) of
O-glucuronides I-IV, but two of the monoxygenated aglycones
liberated by enzymic hydrolysis (beef liver 
-glucuronidase) and
detected by SIM (m/z 253) during LC/MS analysis of the
hydrolysate coeluted with authentic 2- and 3-OH-CBZ
(RT = 39 and 41 min, respectively; fig.
7). Two other peaks in the mass chromatogram for
m/z 253 corresponded to CBZ-E (40 min) and an unidentified
compound (43 min). Studies that used either GC/MS (2) or direct-inlet
MS (14) for the analysis of fractions isolated from human urine resolved four monohydroxy compounds, of which two were identified as 2- and 3-OH-CBZ. The C-1 and C-4 isomers (the latter being only a minor
product) are reported to be urinary metabolites of CBZ (14), but were
not located during the present study. They may have coeluted with the
C-2 isomer (2). In agreement with previous observations (7, 14), CBZ
N-glucuronide was found to be refractory to hydrolysis by
-glucuronidase; no CBZ was detected by SIM analysis of the
hydrolysate. The approximate proportions of glucuronides I-IV, as
determined by integration of the peaks in the Q1 mass chromatogram for
m/z 429, were 0.69, 0.37, 0.37, and 1.0, respectively.
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Fig. 4.
Q2 mass chromatograms (LC/MS/MS) for the
parent (m/z 429, [M + 1]+) and daughter ions of the
glucuronides of monoxygenated CBZ in human urine.
m/z 253 is [M + 1 176]+. V = CBZ-E N-glucuronide.
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Fig. 5.
Parent ion (m/z 429) and CID daughter ion of
the proposed O-glucuronides of monoxygenated CBZ in human urine.
Numerals refer to the peaks in the LC/MS mass chromatogram
for m/z 429 (fig. 2).
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Fig. 6.
CID (LC/MS/MS) spectrum for [M + 1]+ of CBZ-E N-glucuronide (V in fig. 4) in human urine.
Parent ion, m/z 429.
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Fig. 7.
SIM mass chromatograms (LC/MS) for aglycone
metabolites of CBZ in human urine after enzymic hydrolysis of
glucuronides (fig. 2).
Trans-10,11-DHD-CBZ was detected as its protonated molecule
(m/z 271) and dehydrated fragment (m/z 253).
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Glucuronides of Dioxygenated Metabolites.
The Q1 mass chromatograms (fig. 2) for glucuronides of di-OH-CBZ
([M + 1]+ at m/z 445) and OH-methoxy-CBZ
(m/z 459) both contained only one fraction that was
identifiable as a metabolite of CBZ: when fragmented, each conjugate
gave rise to a peak in the mass chromatogram for its respective
protonated aglycone moiety (m/z 269 and m/z 283 respectively; table 2) that was coincident with the peak of the
protonated conjugate. These metabolites, which appeared to be present
at relatively low concentrations, are presumed to be glucuronides of a
catechol (6) and O-methylated catechol (7). Three di-OH-CBZ (catechol) O-glucuronides
and their O-methylated analogs found in human urine have
been characterized as permethylated derivatives (1). Independent
analysis of CBZ metabolites isolated from enzymically hydrolyzed human
urine found four dihydroxy compounds (two of which were assigned to
catechols) and two O-methylated catechols (2, 14).
Glucuronides of Dihydrohydroxy and Dihydrodihydroxy Metabolites.
Only one dihydro-OH-CBZ glucuronide (m/z 431) was found in
each of the three urine samples (fig. 2). At higher cone voltages, the
conjugate fragmented by loss of dehydroglucuronic acid but the
protonated aglycone (m/z 255) was resistant to scission of the carbamoyl group (fig. 8a; table 2), a
spectral pattern considered diagnostic of an O-glucuronide.
Two possible aglycones were considered: 10,11-dihydro-10-OH-CBZ and
9-HM-10-CA (aglycone of 8). However, the former was excluded
by LC/MS analyses of hydrolyzed urine (fig. 7) that established that
none of the peaks in the mass chromatogram for m/z 255 coeluted with the authentic standard (RT = 38 min). The predominant dihydrohydroxy aglycone detected by SIM
(RT = 44 min) eluted after CBZ-E and 3-OH-CBZ in
the manner of 9-HM-10-CA (2). These findings support an earlier
contention that the O-glucuronide of
10,11-dihydro-10-OH-CBZ, which is the major urinary metabolite of
oxcarbazepine in humans (12), is not normally eliminated in human urine
as a product of CBZ (6). Nevertheless, because 10,11-dihydro-10-OH-CBZ
can be converted to 10,11-DHD-CBZ in humans (13), and thereby
constitutes an alternative to CBZ-E as an intermediate in the
biotransformation of CBZ to its principal metabolite, it is possible
that 10,11-dihydro-10-OH-CBZ is formed but not excreted by healthy
subjects. In which case, elimination of the O-glucuronide by
uremic subjects might arise from a deficiency of C-11 hydroxylation.
The glucuronide of 9-HM-10-CA was previously known only in the form of
a decarbamylated artifact of derivatization and GC/MS (1).
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Fig. 8.
(a) ESP mass spectrum (LC/MS) for urinary
metabolite of CBZ assigned to 9-HM-10-CA O-glucuronide (fig 2).
(b) and (c) CID (LC/MS/MS) spectra for [M + 1]+ of the metabolites assigned to OH-9-HM-10-CA
O-glucuronide and 10,11-DHD-CBZ O-glucuronide, respectively (fig. 2).
Parent ions, m/z 447.
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Two dihydrodi-OH-CBZ glucuronides (m/z 447) were located at
RT = 27 and 35 min (fig. 2) in the relative
proportions of 0.24:1.0 (mean; N = 3), but only the
latter was unambiguously identified as a conjugate of a dihydrodiol
(4): it corresponded to a metabolite of CBZ-E in rats (5),
gave ESP and CID spectra (fig. 8c; fig. 9;
table 2) containing a base peak at m/z 253 attributable to
facile dehydration of a dihydrodiol fragment, and yielded on hydrolysis
an aglycone that coeluted with trans-10,11-DHD-CBZ. The
aglycone fragment (m/z 271) of the other dihydrodi-OH-CBZ glucuronide did not dehydrate (fig. 9, table 2), although greater fragmentation was achieved by CID (fig. 8b). The aglycone
liberated by enzymic hydrolysis eluted immediately after
trans-10,11-DHD-CBZ (fig. 7). Whereas the possibility that
this metabolite is a conjugate of a benzenoid dihydrodiol
[i.e. a product of an arene oxide (9)] cannot be
discounted, the absence of facile dehydration constitutes evidence
against such a structure. Instead, it is tentatively identified as a
glucuronide of hydroxylated 9-HM-10-CA (9). The aglycone's
chromatographic behavior resembled that of a metabolite previously
characterized only as an acridan artifact of OH-9-HM-10-CA (2). It was
originally presumed that the ring-contracted carbinol acridans were
formed via the epoxide-diol pathway (1, 2). However,
9-HM-10-CA is only a minor metabolite of CBZ-E in humans (4) and
neither carbinol nor its glucuronide was detected by LC/MS in the urine
or bile of rats given radiolabeled CBZ-E (7) intravenously.2 It has been suggested that
9-HM-10-CA is derived, via a carboxaldehyde, from a
monoxygenated intermediate that is common to the epoxidation and
ring-contraction pathways (15).
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Fig. 9.
Q2 mass chromatograms (LC/MS/MS) for the
parent ion (m/z 447, [M + 1]+) and two daughter ions
of the metabolites of CBZ in human urine assigned to dihydrodi-OH-CBZ
O-glucuronides (fig. 2).
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The glucuronide metabolites of CBZ found in human urine are represented
in fig. 10. Based on the areas of the peaks in their parent-ion ([M + 1]+) chromatograms (fig. 2), the
relative proportions of 8, 4, and 5 (I-IV combined) and 2, 3, 9, and
5 (VI and VII) were 1.0, 0.5, 0.4, 0.33, 0.18, 0.13, and
0.05, respectively (mean for three samples). Although these values are
only uncorrected approximationslargely because no account could be
taken of variations in the instrument response factor between
analytesthe rank order of 4, 5, 2,
and 3 does correspond to that derived from the radiometric
assay of isolated metabolite fractions (14). The notable misalignment
was in respect of 8, which was a minor urinary metabolite in
two volunteers given a single dose of [10,11-14C]CBZ
(14). However, in comparing the metabolite profile of a single
administration and that of chronic therapy, it should be noted that the
metabolism of CBZ via the epoxide-diol pathway in humans is
subject to dose-dependent autoinduction, which attains a maximum during
the first 4 weeks of therapy (16, 17).
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Fig. 10.
Glucuronide metabolites of CBZ
(1) found in human urine.
Arrows and broken arrows indicate, respectively,
major and minor metabolites [relative proportion >0.2 and <0.2,
respectively; (8) = 1.0] as estimated from the areas of
peaks in mass chromatograms (fig. 2); the O-glucuronides of
the six monohydroxylated CBZ derivatives were taken collectively.
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The relevant mass chromatograms were examined for any peaks that might
have corresponded to protonated molecules of cysteinylglycine, cysteinyl, and N-acetylcysteinyl derivatives of CBZ, which,
together with the derivatives' o-hydroxy and dihydrohydroxy
analogs (2), were potential urinary catabolites of glutathionyl
dihydro-OH-CBZ [i.e. the product(s) of the reaction of
glutathione with CBZ's arene oxide intermediate(s)] (7). Diepoxide
formation and sequential epoxidation of CBZ were taken into account by
scanning for the indicative tetrahydrotrihydroxy-thioether adducts
(18). None of these derivatives of epoxides and diepoxides was found,
nor the nonpolar thioethers, sulfoxides, and sulfones identified
previously in either rat (2) or human urine (2, 14). Recent findings on
the bioactivation of CBZ by mouse hepatic microsomes have suggested that the catechol metabolites of CBZ may be oxidized to chemically reactive o-quinones (10). Intermediates of this type are
known to combine with glutathione to form dihydroxythioethers (19), and
they, in turn, might undergo catabolism via the mercapturic acid pathway. Nevertheless, neither a glutathione adduct of di-OH-CBZ nor any of its expected thioether metabolites was detected by LC/MS.
Collectively, this would suggest, at least, that any glutathionyl adducts formed in humans are not appreciably degraded to urinary indicator metabolites; an observation that conforms with the detection of only trace amounts of the nonpolar thio metabolites (2, 14). The
acquisition of substantive metabolic evidence for the bioactivation of
CBZ in humans, and specifically the identification of a glutathione
adduct analogous to those found in rat bile (7), may have to await an
opportunity to characterize the biliary metabolites of CBZ in humans.
| |
Footnotes |
Received March 25, 1996; accepted December 5, 1996.
This study was supported by the Epilepsy Research Foundation
(to M.P.) and by Glaxo Group Research. B.K.P. is a Wellcome Principal Research Fellow. The LC/MS system was purchased with a grant from the
Wellcome Trust.
2
J. L. Maggs, unpublished observation.
Send reprint requests to: Dr. B. K. Park, Department of
Pharmacology and Therapeutics, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, UK.
| |
Abbreviations |
Abbreviations used are:
CBZ, carbamazepine
(5H-dibenz[b,f]azepine-5-carboxamide);
DHD, dihydrodiol;
CBZ-E, carbamazepine-10,11-epoxide;
ESP, electrospray;
SIM, selected ion monitoring;
CID, collision-induced
decomposition;
OH, hydroxy;
9-HM-10-CA, 9-hydroxymethyl-10-carbamoyl
acridan;
Q1 and Q2, 1st and 2nd quadrupoles.
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Abstract
Introduction
Abstract
