Metabolism of Monoamine Oxidase Inhibitors - Springer Link

Cellular and Molecular Neurobiology, Vol. 19, No. 3, 1999

Metabolism of Monoamine Oxidase Inhibitors G. B. Baker,1,3 L. J. Urichuk,1 K. F. McKenna,1 and S. H. Kennedy2 Received February 15, 1997; accepted March 19, 1997; updated February 3, 1999 SUMMARY 1. The principal routes of metabolism of the following monoamine oxidase inhibitors (MAOIs) are described: phenelzine, tranylcypromine, pargyline, deprenyl, moclobemide, and brofaromine. 2. Acetylation of phenelzine appears to be a minor metabolic pathway. Phenelzine is a substrate as well as an inhibitor of MAO, and major identified metabolites of phenelzine include phenylacetic acid and p-hydroxyphenylacetic acid. Phenelzine also elevates brain GABA levels, and as yet unidentified metabolites of phenelzine may be responsible for this effect. b-Phenylethylamine is a metabolite of phenelzine, and there is indirect evidence that phenelzine may also be ring-hydroxylated and N-methylated. 3. Tranylcypromine is ring-hydroxylated and N-acetylated. There is considerable debate about whether or not it is metabolized to amphetamine, with most of studies in the literature indicating that this does not occur. 4. Pargyline and R(2)-deprenyl, both propargylamines, are N-demethylated and N-depropargylated to yield arylalkylamines (benzylamine, N-methylbenzylamine, and N-propargylbenzylamine in the case of pargyline and amphetamine, N-methylamphetamine and N-propargylamphetamine in the case of deprenyl). These metabolites may then undergo further metabolism, e.g., hydroxylation. 5. Moclobemide is biotransformed by C- and N-oxidation on the morpholine ring and by aromatic hydroxylation. An active metabolite of brofaromine is formed by O-demethylation. It has been proposed that another as yet unidentified active metabolite may also be formed in vivo. 6. Preliminary results indicate that several of the MAOIs mentioned above are substrates and/or inhibitors of various cytochrome P450 (CYP) enzymes, which may result in pharmacokinetic interactions with some coadministered drugs. KEY WORDS: monoamine oxidase (MAO); MAO inhibitors; metabolism; phenelzine; tranylcypromine; deprenyl; moclobemide; brofaromine.

INTRODUCTION The monoamine oxidase inhibitors (MAOIs) are not used as extensively as the selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressants in the treatment of mood and anxiety disorders but, nonetheless, have found an important 1

Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2B7, Canada. 2 Clarke Institute, Division of the Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada. 3 To whom correspondence should be addressed. 411 0272-4340/99/0600–0411$16.00/0  1999 Plenum Publishing Corporation

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niche in the armamentarium of clinicians, particularly in the treatment of ‘‘atypical’’ and ‘‘anxious’’ depressions. There has been a resurgence of interest in MAOIs in the past few years, with much of the research and development dealing with selective inhibitors of MAO-A or MAO-B. In the present review, metabolism, an aspect of the MAOIs that is often neglected, is discussed. Despite the exciting advances in MAOI research with regard to the development of new selective MAOIs (both reversible and irreversible), the nonselective irreversible drugs tranylcypromine (TCP) and phenelzine (PLZ) continue as mainstays. However, it is remarkable that, although both of these drugs have been on the market for many years, there is a paucity of information about their metabolism. These two drugs, as well as the irreversible MAO-B-selective inhibitors pargyline and R(2)-deprenyl and the reversible MAO-A-selective inhibitors moclobemide and brofaromine, are the subjects of this review. Isocarboxazid has recently been reintroduced in the U.S.A. for treatment of major depressive disorder, but its metabolism will not be discussed here.

PHENELZINE Phenelzine (PLZ; Nardil) (Fig. 1) is rapidly absorbed, with maximum concentrations occurring 2–4 hr after dosing (Robinson et al., 1985). The plasma elimination half-life is 1.5–4 hr and it has been observed that plasma steady-state levels gradually increase over the initial 6–8 weeks of chronic treatment (Mallinger and Smith, 1991), suggesting that the parent drug (or metabolites) may be inhibiting PLZ’s metabolism (Bieck et al., 1989; Robinson et al., 1978, 1980). Numerous studies have been carried out on the acetylator status of patients and their subsequent response to treatment with PLZ, with contradictory findings obtained (review by Mallinger and Smith, 1991). These investigations have been performed on the assumption that PLZ is acetylated because it is similar in structure to drugs such as isoniazid, which are known to be acetylated. In fact, the existence of N-acetyl-PLZ is a matter of debate, and at best, it appears to be a minor metabolite of PLZ (Narasimhachari et al., 1980; Robinson et al., 1985; Mozayani et al., 1988; Coutts et al., 1991). Results from our laboratory have demonstrated that the acetylation that does occur is at the N2 position of phenelzine (Fig. 1) (Coutts et al., 1991). PLZ is unique in that not only does it inhibit MAO, but also apparently is a substrate for MAO. Clineschmidt and Horita (1969 a,b) proposed that the metabo-

Fig. 1. Structure of phenelzine (I ), N 1-acetylphenelzine (II ), and N 2-acetylphenelzine (III ).

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lite resulting from the action of MAO on PLZ would be phenylacetic acid (Fig. 2). A mass spectrometric study in human subjects confirmed that phenylacetic acid is a major metabolite of PLZ (Robinson et al., 1985). 1-(2-Phenylethyl)diazene (PhCH2CH2N5NH) and phenylethylidene hydrazine (PhCH2CH5NNH2) have also been reported as possible intermediate metabolites formed by the action of MAO on PLZ (Tipton and Spires, 1971; Patek and Hellerman, 1974; Yu and Tipton, 1989). It is interesting in this regard that PLZ, in addition to its inhibition of MAO, produces a marked increase in brain c-aminobutryric acid (GABA) levels and that this action on GABA can be blocked by inhibiting MAO prior to administering PLZ (Popov and Matthies, 1969; Baker et al., 1991; McKenna et al., 1991; Todd and Baker, 1995); these findings indicate that metabolites such as those described immediately above may be responsible for this GABA-elevating action. PLZ also undergoes biotransformation to the bioactive amine b-phenylethylamine (PEA) (Fig. 2) (Baker et al., 1982; Dyck et al., 1985). This is an interesting

Fig. 2. Identified and potential metabolites of phenelzine. Ethylbenzene has also been shown to be a metabolite. Phenylethylidene hydrazine (PhCH2CH 5 NNH2), 1-(2-phenylethyl)diazene (PhCH2CH2N 5 NH), and N-methylphenelzine have also been proposed as metabolites. PLZ, phenelzine; MAO, monoamine oxidase; p-OH-PLZ, p-hydroxyphenelzine, PEA, 2-phenylethylamine; p-TA, p-tyramine; PAA, phenylacetic acid; p-OH-PAA, p-hydroxyphenylacetic acid.

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situation because PEA is also a substrate for MAO, and administration of PLZ results in a dramatic increase in endogenous PEA (e.g., see Philips and Boulton, 1979). Thus it is difficult to ascertain what proportion of the increase in PEA levels observed after PLZ administration is due to inhibition of MAO and what proportion is due to metabolism of PLZ directly to PEA. Another potential metabolic pathway of PLZ that is worthy of further investigation is ring hydroxylation. Although this pathway has never, to our knowledge, been unequivocally demonstrated for PLZ, it seems probable that this conversion does occur since the structurally related drug amphetamine undergoes such metabolism (Axelrod, 1955; Billings et al., 1978; Coutts et al., 1984), and Robinson et al. (1985) found p-hydroxyphenylacetic acid to be a major metabolite of PLZ in humans. p-Hydroxyphenylacetic acid may be formed from phenylacetic acid, a major metabolite of PLZ (Robinson et al., 1985), but it is also possible that some is derived from p-hydroxy-PLZ or from p-tyramine (formed via ring hydroxylation of the PEA resulting from biotransformation of PLZ). Pretreatment of rats with iprindole, an inhibitor of ring hydroxylation, before PLZ administration results in an increase in PLZ brain levels, providing indirect evidence for ring hydroxylation of PLZ (McKenna et al., 1992). A peak with the same retention time as an authentic standard of p-OH-PLZ on gas chromatography was identified in urine samples from PLZ-treated patients (McKenna et al., 1991), but this has not unequivocally been identified as p-OH-PLZ by combined gas chromatography–mass spectrometry (McKenna, 1995). N-Methylation of phenelzine has been demonstrated in vitro (Yu et al., 1991), and ethylbenzene has also been identified as an in vivo and in vitro metabolite of PLZ (Danielson et al., 1984; Ortiz de Montellano and Watanabe, 1987).

TRANYLCYPROMINE Like PLZ, tranylcypromine (TCP; Parnate) is rapidly absorbed and has a short elimination half-life [2 hr in humans (Mallinger et al., 1986)]. As with PLZ, there is also a paucity of information about the metabolism of TCP. In an investigation of TCP and amphetamine, Alleva (1965) reported that 4% of injected 14C-TCP (5 mg/kg) was excreted unchanged, and 12% was excreted as 14C-hippuric acid (corresponding values for amphetamine were 15 and 2%, respectively). Approximately 71% of both drugs were excreted in the urine, primarily as metabolites, within the first day. The presence of hippuric acid as a metabolite implies that the cyclopropyl ring can be opened; however, based on paper chromatographic findings it was concluded that this cleavage does not involve the formation of amphetamine. It was suggested that the ring-opening reaction may involve a liver microsomal enzyme which deaminates alkylamines to ketones (described by Axelrod, 1955). Contrary to the animal study by Alleva (1965), Youdim et al. (1979) reported the detection of amphetamine in the plasma of a TCP overdose victim. There is an assumption in the literature and in some textbooks that amphetamine is a metabolite of TCP (Robinson, 1983; Dilsaver, 1988; Silverstone and Turner, 1995), but this metabolic route has been disputed in several studies (Riederer et al., 1981;

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Mutschler and Mohrke, 1993; Mallinger et al; 1990; Keck et al., 1991, Jefferson, 1992; Iwersen and Schmoldt, 1996). With regard to possible metabolic opening of the cyclopropyl ring, there are three locations at which the ring could be broken, yielding b-methyl-b-phenylethylamine, amphetamine, or phenyl-3-n-propylamine. However, Sherry-McKenna et al. (1992a) were unable to detect phenyl-3-npropylamine as a metabolite of TCP in humans or in rats. N-Acetyl (Calverley et al., 1981) and ring-hydroxylated metabolites of TCP have been reported in rat brain after i.p. administration of TCP (Baker et al., 1986; Nazarali et al., 1987). Kang and Chung (1984), in studies using rat urine, confirmed the formation of N-acetyl-TCP and also identified N-acetyl-p-hydroxyTCP as a TCP metabolite. Foster et al. (1991), in a study on the metabolism of TCP by the fungus Cunninghamella echinulata, reported N-acetyl-TCP and N,Odiacetyl-p-hydroxy-TCP as major metabolites. Structures of these identified metabolites of TCP are shown in Fig. 3. In preliminary studies it has been shown that N-acetyl-TCP and p-OH-TCP retain MAO-inhibiting properties, but are weaker than TCP in this regard, and both metabolites are slightly more potent at inhibiting MAO-A than MAO-B (Baker et al., 1986; Rao et al., 1986). Protection of the para position of the phenyl ring of TCP by substituents such as fluorine and methoxy results in the production of compounds which are still very potent MAOIs but have pharmacokinetic profiles different from that of the parent drug (Coutts et al., 1987; Sherry et al., 1990; Sherry-McKenna et al., 1992b; Sherry-McKenna, 1996). Another area of interest with regard to TCP is the ratio of the enantiomers of this drug in tissues after administration of the racemate (the commercially available form of the drug). The (1)-enantiomer has been shown to be more potent than (2)-TCP at inhibiting MAO, whereas (2)-TCP has been demonstrated to be more effective than (1)-TCP as an inhibitor of uptake of catecholamines (reviews by Smith, 1980; Nickolson and Pinder, 1984). It has also been demonstrated that the individual enantiomers exhibit markedly different pharmacokinetic properties

Fig. 3. Identified metabolites of tranylcypromine.

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such as clearance rates from brain in rats and plasma levels in humans (Fuentes et al., 1976; Reynolds et al., 1980; Lang et al., 1979; Hampson et al., 1986; Mutschler et al; 1990; Spahn-Langguth et al., 1992; Weber-Grandke et al., 1993), but to our knowledge, no one has investigated possible metabolic differences between the two enantiomers.

METABOLISM OF PARGYLINE AND DEPRENYL Pargyline (Eutonyl) and R(2)-deprenyl (Selegiline, Eldepryl) (N-propargyl, N-methyl derivatives of benzylamine and amphetamine, respectively) are used primarily in the treatment of hypertension and Parkinson’s disease, respectively. Removal of the methyl and propargyl groups metabolically has been demonstrated in rodents, humans, and microbes (Durden et al.,1976; Pirisino et al., 1979; Coutts et al., 1981; Philips, 1981; Reynolds et al., 1978a, b; Karoum et al., 1982; Weli and Lindeke, 1986; Yoshida et al., 1986; Lacroix et al., 1994; Heinonen et al., 1994; Lajtha et al., 1996; Masche et al., 1997). With pargyline, the products of this metabolism are benzylamine, N-methylbenzylamine, and N-propargylbenzylamine, while with deprenyl, the metabolites amphetamine, N-methylamphetamine, and N-propargylamphetamine are formed. These metabolites may then undergo some ring and sidechain hydroxylation (Philips, 1981; Lengyel et al., 1997; Shin, 1997; Mahmood, 1997). Karoum (1987) reported that N-propargylbenzylamine is a potent inhibitor of type B MAO in rats in vivo, and N-propargylamphetamine has been reported to have neuroprotective properties (Mytilineou et al., 1997). The structures of pargyline, deprenyl, and their N-dealkylated metabolites are shown in Figs. 4 and 5. In the case of R(2)-deprenyl, the formation of these metabolites has been shown to be

Fig. 4. Structures of pargyline (a) and some of its identified metabolites: N-methylbenzylamine (b), benzylamine (c), and N-propargylbenzylamine (N-desmethylpargyline, norpargyline) (d). These metabolites may undergo further biotransformation (e.g., hydroxylation).

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Fig. 5. Structures of deprenyl (a) and some of its identified metabolites: N-methylamphetamine (b), amphetamine (c), and N-propargylamphetamine (N-desmethyldeprenyl, nordeprenyl) (d). These metabolites may undergo further biotransformation (e.g., hydroxylation).

mediated, at least in part, by cytochrome P450 2D6 (CYP2D6) (Grace et al., 1994; Sharma et al., 1996). Wacher et al. (1996) have recently studied R(2)-deprenyl metabolism in rat and human liver microsomes and concluded that N-depropargylation appears to be mediated almost exclusively by CYP3A, while CYP3A and, to a lesser extent, CYP2D play a role in N-demethylation of this drug.

MOCLOBEMIDE Moclobemide (MOC; Manerix, Aurorix), a benzamide derivative (Fig. 6), was the first of the reversible, selective inhibitors of MAO-A (RIMAs) to become clinically available. This drug is used in over 50 countries worldwide (Dingemanse et al., 1995), albeit not yet in the United States. MOC is only about 50% protein bound and is almost completely absorbed from the GI tract following oral administration, with approximately 95% of the drug cleared renally within 24 hr (Mayersohn and Guentert, 1995). Neither advanced age nor impaired renal function changes plasma concentrations after a MOC dosage, but liver disease drastically decreases the elimination capacity of the liver for MOC (Mayersohn and Guentert, 1995). MOC is extensively metabolized in humans, with less than 1% being excreted in the urine unchanged ( Jauch et al., 1990). The primary routes of metabolism of MOC involve oxidative attack on the morpholine moiety, where C- and N-oxidation, deamination, and aromatic hydroxylation may occur ( Jauch et al., 1990; Mayersohn and Guentert, 1995; Gram et al., 1995) (Fig. 6). Among the known metabolites of MOC, two have been found in human plasma: Ro 12-5637 and Ro 12-8095. Ro 125637, an N-oxide, is generally present only in trace amounts but does retain some MAO-A inhibitory activity. Ro 12-8095 is inactive (Mayersohn and Guentert, 1995). It is important to note that after multiple doses, MOC appears to inhibit its own

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Fig. 6. Simplified schematic of the primary metabolic pathways of moclobemide in humans (adapted from Jauch et al., 1990; Waldmeier et al., 1994).

metabolism. This may be due to inhibition of metabolism by a metabolite of MOC that is formed during its biotransformation (Mayersohn and Guentert, 1995). In vivo, MOC is a highly selective inhibitor of MAO-A, but this inhibition is less pronounced in vitro (Waldmeier et al., 1994), suggesting that a more active, so far unidentified metabolite, might exist in the plasma in the in vivo situation (DaPrada et al., 1989; Waldmeier et al., 1994). Such a possibility is also suggested by the observation that, in the rat, MOC is more potent following oral than subcutaneous administration (DaPrada et al., 1989). Studies have demonstrated that C-hydroxylation of the morpholine ring of MOC, then subsequent lactam formation to yield Ro 12-8095, appears to cosegregate with the CYP2C19 (mephenytoin hydroxylation) polymorphism (Gram et al., 1995; Ha¨rtter et al., 1996). In contrast, the formation of Ro 12-5637, by morpholine N-oxidation, does not appear to be influenced by CYP2C19 phenotype (Gram et al., 1995). Studies have also determined that MOC is an inhibitor of CYP2D6, CYP2C19, and CYP1A2 (Gram and Brøsen, 1993; Gram et al., 1995). It should be noted, however, that even though MOC appears to be quite a potent inhibitor of CYP2D6 in vivo, it has been found to be a relatively weak inhibitor in vitro (Skjelbo and Brøsen, 1992; Gram et al., 1995; Ha¨rtter et al., 1996); such observations suggest

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that a metabolite may be primarily responsible for the effect in vivo. Because many commonly prescribed drugs are substrates for CYP2D6, the inhibition of CYP2D6 produced by MOC could be important if they are coadministered. In addition, the extensive hepatic biotransformation of MOC increases its potential for possible metabolic interactions when administered with other drugs (Ha¨rtter et al., 1996).

BROFAROMINE Brofaromine (BROF) is a tight-binding, reversible inhibitor of MAO-A and has a longer duration of action and considerably more activity in vitro than MOC. Encouraging results have been obtained using BROF as a treatment for major depression (Volz et al., 1994), panic disorder ( Johnson et al., 1994), and social phobia (Gitow et al., 1994), but this drug is not currently marketed. BROF is more highly protein bound than MOC and it has 5-HT reuptake-inhibiting properties in addition to its MAO-inhibiting properties (Waldmeier and Sto¨cklin, 1989; Waldmeier et al., 1993). The major metabolic route for BROF is O-demethylation to O-desmethylbrofaromine via the action of CYP2D6 ( Jedrychowski et al., 1993) (Fig. 7), then subsequent conjugation and excretion. O-Desmethylbrofaromine is an active metabolite that is 6 times more potent than BROF at inhibiting 5-HT uptake but 100 times less potent at inhibiting MAO-A in rat brain (Bieck et al., 1993; Waldmeier et al., 1994). O-Desmethylbrofaromine is extensively conjugated and the resultant derivative accounts for about 40% of the administered dose of BROF, with another 40% of the dose attributed to unchanged BROF and less than 3% to other unconjugated metabolites (Waldmeier et al., 1994). Total renal excretion accounts for 76% of an oral dose of BROF (Bieck et al., 1993).

POTENTIAL FOR PHARMACOKINETIC DRUG–DRUG INTERACTIONS WITH THE MONOAMINE OXIDASE INHIBITORS Although considerable research has been conducted on pharmacodynamic interactions between MAOIs and coadministered drugs, pharmacokinetic interactions with the MAOIs have been largely neglected. It is certainly possible that patients taking MAOIs will be receiving other drugs such as neuroleptics, anxiolytics, or tricyclic antidepressants, which are extensively metabolized, and that, through interference with each other’s metabolism, these drugs and the MAOIs may be modifying each other’s concentrations in plasma and in organs such as the brain and heart. Such interactions have been well documented when tricylic antidepressants, phenothiazine neuroleptics, or SSRI antidepressants are given in combination with each other (reviews by Harvey and Preskorn, 1996a, b; Lane, 1996). There are several reports in the literature indicating that TCP and PLZ interact with enzyme systems involved in both N-demethylation and ring hydroxylation (e.g., Eade and Renton, 1970; Belanger and Atitse-Gbeassor, 1982; Dupont et al., 1987). Baker et al. (1986) demonstrated that phenothiazine antipsychotics cause an increase in brain

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Fig. 7. Structures of some metabolites of brofaromine in humans (adapted from Waldmeier et al., 1994).

levels of TCP when coadministered with this MAOI. TCP has been reported to be a relatively potent inhibitor of mephenytoin hydroxylase (Inaba et al., 1985), a CYP isozyme now called CYP2C19 (Goldstein et al., 1994), which is responsible for metabolism of a number of drugs. The combination of SSRI antidepressants and MOC has demonstrated good efficacy in cases of refractory depression but has created controversy as to whether or not toxic side effects such as serotonin syndrome result from the combination (Bakish et al., 1995; Liedenberg et al., 1996; Dingemanse, 1993). Recently, an adverse reaction was reported to occur after 4 weeks of concomitant use of fluoxetine and MOC (see Liedenberg et al., 1996). This latent response may have been due to the fact that, after a week of multiple dosing, the clearance of MOC decreases (apparently due to inhibition of MOC metabolism by the parent drug or a metabolite) (Hyman et al., 1995). Thus, MOC accumulation may have inhibited the CYP iso-

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zyme(s) involved in fluoxetine metabolism, resulting in increased levels of fluoxetine and possible resultant adverse effects (Liedenberg et al., 1996). A study examining possible interactions between MOC and fluvoxamine, a SSRI with a shorter elimination half-life than fluoxetine, found that this combination resulted in increased plasma levels of MOC (review by Dingermanse, 1993). In addition, when given with the potent CYP inhibitor cimetidine, up to a 50% decrease in the clearance of MOC has been reported (Zimmer et al., 1990; Schoerlin et al., 1991); in fact a reduction of MOC to one-half of the usual dose is recommended when the drug is given in combination with cimetidine (Gillis, 1997). As BROF is not currently marketed, there is a paucity of metabolic interaction data available on this drug. However, because BROF is a substrate for CYP2D6, it has the potential to interact with numerous drugs that are also substrates for this enzyme if the drugs are administered concomitantly.

CONCLUSIONS It is clear that much remains to be investigated with regard to the nature and extent of metabolism of MAOIs. It is conceivable that the metabolites formed are contributing to the therapeutic and side-effect profiles as well as to possible drug interactions. In addition, as with other drugs; the effect of the presence of a chiral center on the distribution, elimination, and metabolism of drugs such as TCP should be considered. It seems obvious that a greater understanding of the metabolism of this diverse class of drugs could result in improved treatment of depression in the future and could also provide valuable clues to help explain behavioral observations that have been made in humans and laboratory animals treated with these drugs, either alone or in combination with other drugs.

ACKNOWLEDGMENTS Funds for the authors’ research have been provided by the Medical Research Council of Canada, the Canadian Psychiatric Research Foundation, the Alberta Mental Health Research Fund, and the Alberta Heritage Foundation for Medical Research. The authors are grateful to Mrs. P. Wolfaardt for typing the manuscript, to Ms. J. van Muyden for preparing the diagrams, and to Ms. G. Rauw for expert technical assistance in drug metabolism studies.

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