Biotransformation of moclobemide in humans
`Biotransformation of moclobemide in humans
`
`Jauch R, Griesser E, Oesterhelt G, Arnold W, Meister W, Ziegler WH,
`Guentert TW. Biotransformation of moclobemide in humans.
`Acta Psychiatr Scand 1990. Suppl 360: 87-90.
`The structure of the urinary metabolites formed after moclobemide ad-
`The structure of the urinary metabolites formed after moclobemide ad-
`ministration in humans was elucidated, and the pattern compared with that
`ministration in humans was elucidated, and the pattern compared with that
`in the plasma. The metabolic pathways of moclobemide were also com-
`in the plasma. The metabolic pathways of moclobemide were also com-
`pared with those of structurally related substances. After oral moclobemide
`pared with those of structurally related substances. After oral moclobemide
`administration, on average 95% of the dose was recovered in the urine
`administration, on average 95% of the dose was recovered in the urine
`within 4 days, with a mean of 92% being excreted during the first 12 h.
`within 4 days, with a mean of 92% being excreted during the first 12 h.
`The drug is extensively metabolized: less than 1 % of the dose was excreted
`The drug is extensively metabolized: less than 1% of the dose was excreted
`unchanged. A total of 19 metabolites, accounting together for about
`unchanged. A total of 19 metabolites, accounting together for about
`64% of the dose, was isolated and all metabolites accounting for more
`64% of the dose, was isolated and all metabolites accounting for more
`than 170 of the dose were identified. Consistent with other morpholine-
`than 1% of the dose were identified. Consistent with other morpholine-
`containing compounds, metabolic pathways of moclobemide include
`containing compounds, metabolic pathways of moclobemide include
`mainly oxidative attack on the morpholine moiety, leading to a multitude
`mainly oxidative attack on the morpholine moiety, leading to a multitude
`of oxidation products. Four primary metabolic reactions were identified:
`of oxidation products. Four primary metabolic reactions were identified:
`morpholine N-oxidation, aromatic hydroxylation, morpholine C-oxi-
`morpholine N-oxidation, aromatic hydroxylation, morpholine C-oxi-
`dation and deamination. The major metabolites in urine are 4 carboxylic
`dation and deamination. The major metabolites in urine are 4 carboxylic
`acids (M7A and M7B, M8, M9) that account for 49% of the dose. Only
`acids (M7A and M7B, M8, M9) that account for 49% of the dose. Only
`2 metabolites (M3, MlO) were found to be hydroxylated on the aromatic
`2 metabolites (M3, M10) were found to be hydroxylated on the aromatic
`nucleus. They were excreted completely as conjugates of glucuronic and/
`nucleus. They were excreted completely as conjugates of glucuronic and/
`or sulfuric acid. Conjugation in general, however, seems to be of minor
`or sulfuric acid. Conjugation in general, however, seems to be of minor
`importance in the overall biotransformation of the drug. The metabolite
`importance in the overall biotransformation of the drug. The metabolite
`pattern in plasma was found to be qualitatively but not quantitatively
`pattern in plasma was found to be qualitatively but not quantitatively
`similar to that observed in urine. Almost all of the main urinary metabo-
`similar to that observed in urine. Almost all of the main urinary metabo-
`lites were found in plasma as well. The unchanged parent compound and
`lites were found in plasma as well. The unchanged parent compound and
`2 primary oxidation products of the morpholine ring (Ml, MlS), which
`2 primary oxidation products of the morpholine ring (M1, M15), which
`were present in urine only in trace amounts, could easily be detected in
`were present in urine only in trace amounts, could easily be detected in
`I plasma.
`plasma.
`
`R. Jauch', E. Griesser', 6. Oesterhelt',
`R. Jauch', E. Griesser', G. Oesterhelt',
`W. Arnold', W. Meister',
`W. Arnold', W. Meister',
`W. H. Ziegier*, T. W. Guenterf'
`W. H. Ziegler', T. W. Glinted"
`'Research Department, 3Department of Clinical
`'Research Department, 'Department of Clinical
`Pharmacology, F. Hoff mann-La Roche, Basle, 'Divi-
`Pharmacology, F. Hoffmann-La Roche, Basle, 'Divi-
`sion ot Clinical Pharmacology, University Hospi-
`sion of Clinical Pharmacology, University Hospi-
`tal, Zurich, Switzerland
`tal, Zurich, Switzerland
`
`Key words: antidepressant; moclobemide; meta-
`Key words: antidepressant; moclobemide; meta-
`bolism; morpholine
`bolism; morpholine
`R. Jauch, Research Department, F. Hoffmann-La
`R. Jauch, Research Department, F. Hoffmann-La
`Roche, CH-4002 Basle, Switzerland
`Roche, CH-4002 Basle, Switzerland
`
`Moclobemide belongs to a new generation of
`Moclobemide belongs to a new generation of
`monoamine oxidase (MAO) inhibitors of the
`monoamine oxidase (MAO) inhibitors of the
`benzamide type and contains a morpholine ring as
`benzamide type and contains a morpholine ring as
`a characteristic part of its structure.
`a characteristic part of its structure.
`The aim of this study was to elucidate the struc-
`The aim of this study was to elucidate the struc-
`tures of the urinary metabolites formed from mo-
`tures of the urinary metabolites formed from mo-
`clobemide after its administration to humans and
`clobemide after its administration to humans and
`to compare the metabolite pattern in urine and
`to compare the metabolite pattern in urine and
`plasma. In addition, a comparison of metabolic
`plasma. In addition, a comparison of metabolic
`pathways between moclobemide and structurally
`pathways between moclobemide and structurally
`related drugs was attempted.
`related drugs was attempted.
`
`Material and methods
`Material and methods
`Drug administration and sample collection
`Drug administration and sample collection
`Two healthy young volunteers received 50 mg 14C-
`Two healthy young volunteers received 50 mg '4C-
`labelled moclobemide (2 pCi/mg; position of radio-
`labelled moclobemide (2 pEi/mg; position of radio-
`label, see Fig. 1) orally in a hard gelatine capsule.
`label, see Fig. 1) orally in a hard gelatine capsule.
`Blood was taken by puncture of an arm vein at
`Blood was taken by puncture of an arm vein at
`different time points up to 10 h after administra-
`different time points up to 10 h after administra-
`tion and plasma was obtained by centrifugation.
`tion and plasma was obtained by centrifugation.
`
`Urine and faeces were collected quantitatively in
`Urine and faeces were collected quantitatively in
`fractions up to 96 h after administration.
`fractions up to 96 h after administration.
`
`Isolating and identifying the metabolites
`Isolating and identifying the metabolites
`Metabolites were isolated from pooled 0-12 h urine
`Metabolites were isolated from pooled 0-12 h urine
`by chromatography on Amberlite XAD-2 resin
`by chromatography on Amberlite XAD-2 resin
`and subsequent extractions with ethyl acetate at
`and subsequent extractions with ethyl acetate at
`pH 9 and pH 3. These extractions were made be-
`pH 9 and pH 3. These extractions were made be-
`fore and after enzymatic hydrolysis with a mixture
`fore and after enzymatic hydrolysis with a mixture
`of beta-glucuronidase and arylsulfatase. Separ-
`of beta-glucuronidase and arylsulfatase. Separ-
`ation and purification of the metabolites were
`ation and purification of the metabolites were
`achieved by preparative thin-layer chromatogra-
`achieved by preparative thin-layer chromatogra-
`phy (TLC) on silica gel. Structures were identified
`phy (TLC) on silica gel. Structures were identified
`by using radio-GC, GC/MS, MS and 'H-NMR.
`by using radio-GC, GC/MS, MS and 'H-NMR.
`Migration distances on TLC compared with refer-
`Migration distances on TLC compared with refer-
`ence compounds were an important additional tool
`ence compounds were an important additional tool
`to get a first hint for possible structures or chemical
`to get a first hint for possible structures or chemical
`nature of a compound. Derivatization reactions
`nature of a compound. Derivatization reactions
`on isolated metabolites and/or synthetic reference
`on isolated metabolites and/or synthetic reference
`compounds facilitated structure elucidations in
`compounds facilitated structure elucidations in
`87
`87
`
`MYLAN - EXHIBIT 1029
`
`

`
`several cases. All metabolites accounting for more
`several cases. All metabolites accounting for more
`than 1% of the dose were identified.
`than 1% of the dose were identified.
`In plasma (0.5-4 h pool: not hydrolyzed enzy-
`In plasma (0.5-4 h pool: not hydrolyzed enzy-
`matically) the metabolite pattern was investigated
`matically) the metabolite pattern was investigated
`by analytical TLC on silica gel.
`by analytical TLC on silica gel.
`
`Results and discussion
`Results and discussion
`Administration of ''C-labelled moclobemide al-
`Administration of 14C-labelled moclobemide al-
`lowed investigation of the mass balance of ex-
`lowed investigation of the mass balance of ex-
`cretion, determination of major excretory routes
`cretion, determination of major excretory routes
`and subsequent metabolite
`identification and
`and subsequent metabolite identification and
`quantification.
`quantification.
`
`Mass balance of excretion
`Mass balance of excretion
`Following the oral administration of 50 mg moclo-
`Following the oral administration of 50 mg moclo-
`bemide, a mean of 95% of the dose was excreted
`bemide, a mean of 95% of the dose was excreted
`in urine within the 96 h collection period, 92%
`in urine within the 96 h collection period, 92%
`within the first 12 h. Combined total urinary and
`within the first 12 h. Combined total urinary and
`faecal recovery of drug-related material accounted
`faecal recovery of drug-related material accounted
`for all of the drug dose. Before excretion the drug
`for all of the drug dose. Before excretion the drug
`was almost entirely metabolized; at most 0.4% of
`was almost entirely metabolized; at most 0.4% of
`the dose was excreted as intact moclobemide in
`the dose was excreted as intact moclobemide in
`urine.
`urine.
`
`Urinary metabolites
`Urinary metabolites
`A multitude of different moclobemide metabolites
`A multitude of different moclobemide metabolites
`are formed in the metabolic degradation of the
`are formed in the metabolic degradation of the
`drug (Fig. 1). Four distinct groups of compounds
`drug (Fig. 1). Four distinct groups of compounds
`could be identified in urine by 2-dimensional TLC:
`could be identified in urine by 2-dimensional TLC:
`acidic (49% of dose), neutral (8%), basic (2%)
`acidic (49% of dose), neutral (8%), basic (2%)
`compounds and N-oxides (4.5%). A total of 19
`compounds and N-oxides (4.5%). A total of 19
`metabolites were identified, accounting together
`metabolites were identified, accounting together
`for about 64% of the dose.
`for about 64% of the dose.
`The metabolic cascade is initiated by 4 primary
`The metabolic cascade is initiated by 4 primary
`reactions: morpholine N-oxidation, aromatic hy-
`reactions: morpholine N-oxidation, aromatic hy-
`droxylation, morpholine C-oxidation and deamin-
`droxylation, morpholine C-oxidation and deamin-
`ation. Quantitatively, the products of the oxidation
`ation. Quantitatively, the products of the oxidation
`of the morpholine ring are particularly prominent.
`of the morpholine ring are particularly prominent.
`They can all be considered to be derived from a
`They can all be considered to be derived from a
`metabolic product with a single hydroxyl group in
`metabolic product with a single hydroxyl group in
`the morpholine moiety (MI). The position of this
`the morpholine moiety (M1). The position of this
`substituent has not been established. By further
`substituent has not been established. By further
`oxidation of the alcoholic group and additional
`oxidation of the alcoholic group and additional
`oxidative attacks in the heterocyclic ring several
`oxidative attacks in the heterocyclic ring several
`metabolites with a lactam structure (neutral com-
`metabolites with a lactam structure (neutral com-
`pounds, M 1 1, M 13-M 16) are formed. Ring open-
`pounds, M 11, M13—M16) are formed. Ring open-
`ing via hypothetical intermediate aldehydes leads
`ing via hypothetical intermediate aldehydes leads
`to carbamides, tertiary and secondary amines. The
`to carbamides, tertiary and secondary amines. The
`
`primary metabolic
`reactior,s
`
`oxidatior.s
`
`nng
`
`CI (cid:9)
`
`0 H
`N CH, CH;-N
`0)
`°
`
`M5. 3 5% (cid:9)
`
`c-011cH,-CH,Nr
`4/o
`0 OH
`
`M6 1%
`
`P. c B
`
`c
`ti
`
`0 (cid:9)
`
`CI
`
`HO
`
`9
`C N CH, CH,-0N)- )
`
`MIO 3%
`
`OH .0.04011.
`
`R-CH,-
`M161%
`
`•
`
`
`
`R-CH,-N 0 (cid:9)
`
`M15.- 1%
`
`\
`
`R_cH,-:>:0....R-cHz,-:), jc)--•0
`:::::: 00,4;11 .
`"0 .0 HO
`\
`
`n
`0
`He—
`R -CH,.-N.H 0
`
`reductions. oxidations
`
`4 (cid:9)
`
`R CI
`
`OH
`
`0
`
`•
`
`0
`
`,C-CH,OH
`R-CH -N
``CH,-CH,OH
`M18.1%
`
`C-CH,OH
`
`M12 1%
`
`-
`
`0
`C-CHO
`CH,-CH,OH
`
`R-CH,-N'
`
`O
`C-H
`R-CH,-Ps(
`CH,CH,OH
`P.117,1%
`
`/ (cid:9)
`
`c400
`IC-COON'
`'04,-CH,OH
`"CH,-CH,OH
`M B 3! V o
`MS 31%
`
`R-C
`11,-K
`
`XH,OH
`"
`CH,-CH,OH
`24,
`M4. 25.
`
`0 H
`it (cid:9) I
`C-N-CH
`M1
`
`),--Ndr (cid:9)
`
`)-1
`ON
`M14. < 1%
`
`"%•.4....... (cid:9)
`
`-N,/ CH, -COON
`8-CH
`\ CH,-CH,OH
`M7 A. 11%
`
`1 I
`
`CH,--Cnc
`s ch,4"CH,-CHO
`- C h , d
`\CH,--CH OH
`\ CH,-CH.OH
`L
`J
`
`0 (cid:9)
`
`(11
`M9. 7',
`Fig. I. Structures and possible biogenetic pathways of the metabolites of moclobemide in humans. The scheme relates to urinary
`Fig. I. Structures and possible biogenetic pathways of the metabolites of moclobemide in humans, The scheme relates to urinary
`metabolites. Structures with framed designation were found in plasma as well. Percentages relate urinary recovery of a metabolite
`to the dose administered. [ ] hypothetical intermediate; * position of the "C-label.
`metabolites. Structures with framed designation were found in plasma as well. Percentages relate urinary recovery of a metabolite
`to the dose administered. [ ] hypothetical intermediate; * position of the 14C-label.
`88
`88
`
`_vCH-CH.OH
`R_CH,
`\ CH -CH,01-1
`M2 < 15.
`
`(cid:9)
`

`
`4 most important excretion products in the urine
`4 most important excretion products in, the urine
`(M8, M7A and M7B, M9) are all carboaylic acids
`(M8, M7A and M7B, M9) are all carboxylic acids
`accounting together for 49% of the administered
`accounting together for 49% of the administered
`dose (Fig. 1). Besides oxidation of the aliphatic
`dose (Fig. 1). Besides oxidation of the aliphatic
`part of the molecule, oxidation of the aromatic
`part of the molecule, oxidation of the aromatic
`ring was also observed, albeit to a lesser extent.
`ring was also observed, albeit to a lesser extent.
`The phenols thus formed do not appear as free
`The phenols thus formed do not appear as free
`compounds. They are excreted into the ,urine al-
`compounds. They are excreted into the urine al-
`most exclusively in the form of conjugates with
`most exclusively in the form of conjugates with
`glucuronic and/or sulfuric acid.
`,
`glucuronic and/or sulfuric acid.
`
`Metabolites in plasma
`Metabolites in plasma
`A comparison of the concentrations of parent drug
`A comparison of the concentrations of parent drug
`and total radioactivity in plasma indicated that a
`and total radioactivity in plasma indicated that a
`large fraction of the radioactivity could not be
`large fraction of the radioactivity could not be
`accounted for by unchanged drug. The metabolic
`accounted for by unchanged drug. The metabolic
`pattern of drug-related compounds in the plasma
`pattern of drug-related compounds in the plasma
`pool revealed, besides parent drug, a variety of
`pool revealed, besides parent drug, a variety of
`circulating metabolites. Overall, the pattern of
`circulating metabolites. Overall, the pattern of
`metabolites in plasma was qualitatively similar to
`metabolites in plasma was qualitatively similar to
`that in urine. Among the metabolites identified in
`that in urine. Among the metabolites identified in
`plasma were the main urinary metabolites, namely
`plasma were the main urinary metabolites, namely
`the acids M8, M7A, M9, and, in traces, the MAO-
`the acids M8, M7A, M9, and, in traces, the MAO-
`A-inhibiting N-oxide M5. The MAO-B-inhibiting
`A-inhibiting N-oxide M5. The MAO-B-inhibiting
`M4 was also detected in plasma, but it is not clear
`M4 was also detected in plasma, but it is not clear
`at present whether the concentrations found for
`at present whether the concentrations found for
`this product were real or artifactually enhanced
`this product were real or artifactually enhanced
`because of a labile precursor. Nevertheless, as
`because of a labile precursor. Nevertheless, as
`judged from autoradiograms of the TLC plates, in
`judged from autoradiograms of the TLC plates, in
`plasma one of the major metabolites was the lac-
`plasma one of the major metabolites was the lac-
`tam derivative M15, a compound accounting for
`tam derivative M15, a compound accounting for
`less than 1 % of the dose in urine. This supports the
`less than 1% of the dose in urine. This supports the
`assumption that M 15 is an early but still relatively
`assumption that M15 is an early but still relatively
`lipophilic metabolite undergoing further degrada-
`lipophilic metabolite undergoing further degrada-
`tion to mainly acids (Fig. 1).
`tion to mainly acids (Fig. 1).
`
`Metabolite activity
`Metabolite activity
`Several of the key products in the moclobemide
`Several of the key products in the moclobemide
`metabolism are acids with no activity. Only moclo-
`metabolism are acids with no activity. Only moclo-
`bemide-N-oxide M5 retains some MAO-A-inhibi-
`bemide-N-oxide M5 retains some MAO-A-inhibi-
`tory activity; the ring-opened metabolites M2 and
`tory activity; the ring-opened metabolites M2 and
`M4 were found to inhibit MAO-B in rat liver. It is
`M4 were found to inhibit MAO-B in rat liver. It is
`important to notice that M15, one of the main
`important to notice that M15, one of the main
`moclobemide metabolites in plasma, is practically
`moclobemide metabolites in plasma, is practically
`inactive.
`inactive.
`
`Comparison of the metabolism of moclobemide with other
`Comparison of the metabolism of moclobemide with other
`compounds containing the morpholine moiety
`compounds containing the morpholine moiety
`The metabolism of moclobemide was compared
`The metabolism of moclobemide was compared
`with that of compounds with a similar structure.
`with that of compounds with a similar structure.
`From studies with a variety of compounds carrying
`From studies with a variety of compounds carrying
`a morpholine moiety, a general pattern of meta-
`a morpholine moiety, a general pattern of meta-
`bolic degradation reactions emerges. Carbon
`bolic degradation reactions emerges. Carbon
`atoms with one or more H-atoms and alpha-posi-
`atoms with one or more H-atoms and alpha-posi-
`
`tioned to heteroatoms are susceptible, in general,
`tioned to heteroatoms are susceptible, in general,
`to metabolic oxidation. In the morpholine ring
`to metabolic oxidation. In the morpholine ring
`such oxidative reactions lead to lactams and lac-
`such oxidative reactions lead to lactams and lac-
`tones (1). Multiple oxidative attack leads to forma-
`tones (1). Multiple oxidative attack leads to forma-
`tion of highly oxidized morpholine ring systems
`tion of highly oxidized morpholine ring systems
`and ring opening. Tatsumi et al. (2) were the first
`and ring opening. Tatsumi et al. (2) were the first
`to identify dioxygenated derivatives of the mor-
`to identify dioxygenated derivatives of the mor-
`pholine ring; opening of the ring system had al-
`pholine ring; opening of the ring system had al-
`ready been established earlier (3). The oxidative
`ready been established earlier (3). The oxidative
`reactions at the morpholine ring result in formation
`reactions at the morpholine ring result in formation
`of substantial amounts of acids (4). Most metabo-
`of substantial amounts of acids (4). Most metabo-
`lites formed by oxidative reactions are excreted in
`lites formed by oxidative reactions are excreted in
`unconjugated form.
`unconjugated form.
`Moclobemide metabolism in humans follows
`Moclobemide metabolism in humans follows
`this general pattern of morpholine oxidation. Both
`this general pattern of morpholine oxidation. Both
`oxidation reactions seem to occur at the morpho-
`oxidation reactions seem to occur at the morpho-
`line substituent as intermediate steps in the meta-
`line substituent as intermediate steps in the meta-
`bolic cascade (see Fig. l: formation of M15 and
`bolic cascade (see Fig. 1: formation of M15 and
`M7A) followed by further oxidation and ring open-
`M7A) followed by further oxidation and ring open-
`ing. Although a 2,3-dioxo-morpholine derivative
`ing. Although a 2,3-dioxo-morpholine derivative
`analogous to Tatsumi’s structure (2) was not found
`analogous to Tatsumi's structure (2) was not found
`with moclobemide in the ring-closed form, several
`with moclobemide in the ring-closed form, several
`closely related polyoxygenated derivatives were
`closely related polyoxygenated derivatives were
`identified (M11, M13, M14 and M16). As expected,
`identified (M11, M13, M14 and M16). As expected,
`acids account for a large fraction of excreted oxi-
`acids account for a large fraction of excreted oxi-
`dation products; in fact, the 2 major metabolites
`dation products; in fact, the 2 major metabolites
`in urine M8 and M7A are acids.
`in urine M8 and M7A are acids.
`Comparing the metabolism of moclobemide
`Comparing the metabolism of moclobemide
`with that of other morpholine derivatives reveals
`with that of other morpholine derivatives reveals
`a high degree of similarity. In the case of timolol,
`a high degree of similarity. In the case of timolol,
`a beta-blocking agent, and molsidomine, a potent
`a beta-blocking agent, and molsidomine, a potent
`antianginal drug, the major metabolite corre-
`antianginal drug, the major metabolite corre-
`sponds to a major product seen with moclobemide
`sponds to a major product seen with moclobemide
`(M7A) ($6). Many similarities can be found in the
`(M7A) (5, 6). Many similarities can be found in the
`metabolism of moclobemide and that of trithiozine
`metabolism of moclobemide and that of trithiozine
`(7). Extensive oxidation of the morpholine moiety,
`(7). Extensive oxidation of the morpholine moiety,
`ring-opening and stepwise breakdown was also
`ring-opening and stepwise breakdown was also
`found with this thiobenzamide derivative that re-
`found with this thiobenzamide derivative that re-
`duces gastric acid secretion. Although this com-
`duces gastric acid secretion. Although this com-
`pound has several metabolically labile methoxy
`pound has several metabolically labile methoxy
`groups, at least 23% of the dose undergoes oxida-
`groups, at least 23% of the dose undergoes oxida-
`tive changes in the morpholine moiety (moclobem-
`tive changes in the morpholine moiety (moclobem-
`ide > 55%); a considerable portion of the dose was
`ide > 55%); a considerable portion of the dose was
`excreted in urine as acids. The compound anal-
`excreted in urine as acids. The compound anal-
`ogous in structure to a major moclobemide meta-
`ogous in structure to a major moclobemide meta-
`bolite in humans (ring-opened acid M7A; l l % of
`bolite in humans (ring-opened acid M7A; 11% of
`the dose) was also found to be a major metabolite
`the dose) was also found to be a major metabolite
`of trithiozine (6%). Again, as found for moclobem-
`of trithiozine (6%). Again, as found for moclobem-
`ide, most metabolites of trithiozine with altered
`ide, most metabolites of trithiozine with altered
`morpholine ring were excreted in unconjugated
`morpholine ring were excreted in unconjugated
`form. The metabolic degradation of the morpho-
`form. The metabolic degradation of the morpho-
`line ring of emorfazone (8) is another example of
`line ring of emorfazone (8) is another example of
`close similarities with moclobemide. Several of the
`close similarities with moclobemide. Several of the
`metabolites of moclobemide in humans (Ml, M2,
`metabolites of moclobemide in humans (M1, M2,
`M4, M7A) were found in analogous structures of
`M4, M7A) were found in analogous structures of
`this anti-inflammatory. For both compounds the
`this anti-inflammatory. For both compounds the
`89
`89
`
`

`
`main metabolite in humans resulted from identical
`main metabolite in humans resulted from identical
`metabolic degradation of the morpholine ring.
`metabolic degradation of the morpholine ring.
`
`Conclusion
`Conclusion
`After oral moclobemide administration, on aver-
`After oral moclobemide administration, on aver-
`age 95% of the dose was recovered in the urine
`age 95% of the dose was recovered in the urine
`within 4 days, with a mean of 92% being excreted
`within 4 days, with a mean of 92% being excreted
`during the first 12 h. The drug is extensively meta-
`during the first 12 h. The drug is extensively meta-
`bolized: less than l % of the dose was excreted
`bolized: less than 1% of the dose was excreted
`unchanged. Nineteen metabolites accounting to-
`unchanged. Nineteen metabolites accounting to-
`gether for about 64% of the dose were isolated and
`gether for about 64% of the dose were isolated and
`all metabolites accounting for more than I % of
`all metabolites accounting for more than 1% of
`the dose were identified. Consistent with other
`the dose were identified. Consistent with other
`morpholine-containing compounds, metabolic
`morpholine-containing compounds, metabolic
`pathways of moclobemide include mainly oxidative
`pathways of moclobemide include mainly oxidative
`attack on the morpholine moiety, leading to a mul-
`attack on the morpholine moiety, leading to a mul-
`titude of oxidation products. Four primary meta-
`titude of oxidation products. Four primary meta-
`bolic reactions were identified: morpholine N-oxi-
`bolic reactions were identified: morpholine N-oxi-
`dation, aromatic hydroxylation, morpholine C-oxi-
`dation, aromatic hydroxylation, morpholine C-oxi-
`dation, deamination. The major metabolites in
`dation, deamination. The major metabolites in
`urine are 4 carboxylic acids (M7A and M7B, M8,
`urine are 4 carboxylic acids (M7A and M7B, M8,
`M9) that account for 49% of the dose. Only 2
`M9) that account for 49% of the dose. Only 2
`metabolites (M3, M10) were found to be hydroxyl-
`metabolites (M3, M10) were found to be hydroxyl-
`ated on the aromatic nucleus. They were excreted
`ated on the aromatic nucleus. They were excreted
`completely as conjugates of glucuronic and/or sulf-
`completely as conjugates of glucuronic and/or sulf-
`uric acid. Conjugation in general, however, seems
`uric acid. Conjugation in general, however, seems
`to be of minor importance in the overall biotrans-
`to be of minor importance in the overall biotrans-
`formation Gf the drug. The metabolite pattern in
`formation of the drug. The metabolite pattern in
`plasma was found to be qualitatively but not quan-
`plasma was found to be qualitatively but not quan-
`titatively similar to that observed in urine. Almost
`titatively similar to that observed in urine. Almost
`all of the main urinary metabolites were found in
`all of the main urinary metabolites were found in
`
`plasma as well. The unchanged parent compound
`plasma as well. The unchanged parent compound
`and 2 primary oxidation products of the morpho-
`and 2 primary oxidation products of the morpho-
`line ring (Ml, M15), which were present in urine
`line ring (M1, M15), which were present in urine
`only in trace amounts, could easily be detected in
`only in trace amounts, could easily be detected in
`plasma.
`plasma.
`
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`
`90