EDITORIAL
Br. J. clin. Pharmac. (1979), 7,451-452
PHENELZINE: ACETYLATOR STATUS AND CLINICAL RESPONSE Acetylation is an important route of metabolism and thus drug elimination. More than one enzyme system is involved in acetylation, but N-acetyl transferase has been shown to acetylate a number of aromatic amines including isoniazid, sulphadimidine, sulphapyridine, dapsone, hydrallazine and procainamide (Lund, Frislid & Hansteen, 1977). N-acetyl transferase, though mainly present in the liver, can be found also in the gastrointestinal mucosa and may be present in other tissues. Since phenelzine is a amine, with a chemical structure similar to that of several compounds undergoing acetylation (Figure 1), it has been proposed that it may also undergo metabolism by N-acetyl transferase (Evans, Davison & Pratt, 1965). However, the acetylated derivative of phenelzine, acetyl phenelzine, has yet to be identified as a metabolite in either man or any other animal (Marshall, 1976), and it is only recently that quantitation of phenelzine in urine has been possible. An assay (Caddy, Stead & Johnstone, 1978) which measures the parent compound and certain nonacetylated derivatives, has shown that less than 5% of the drug is excreted in these forms which suggests extensive metabolism. Tilstone, Margot & Johnstone (1979) have suggested from indirect evidence that acetylphenelzine is produced when homogenates of rat and human liver are incubated with phenelzine in vitro. However, their methodology did not include identification or measurement of acetylphenelzine. N-acetyl transferase activity shows genetic variation, and populations can be divided into two phenotypes (fast or slow acetylators) though the ratio varies. Evans Marley & McKusick, (1960) investigated the genetic control of isoniazid metabolism and showed that slow acetylators are autosomal homozygous recessive while fast acetylators are either heterozygous or homozygous dominant. Thus, slow acetylators will have higher plasma concentrations of the parent drug and lower concentrations of the acetylated metabolite: they may therefore show therapeutic responses at lower doses than rapid acetylators. Moreover, slow acetylators will be a greater risk from adverse reactions due to the parent compound (such as isoniazid peripheral neuropathy) (Devadatta, Gangadharum, Andrews, Fox, Ramakrishnan, Selkon & Velu, 1960), whilst rapid acetylators will be at greater risk from adverse reactions due to the acetylated metabolites (such as isoniazid hepatitis) (Mitchell, Thorgeirrsson, Black, Timbrell, Snodgrass, Potter, Jollow & Keiser, 1975). Because of the difficulties in measuring phenelzine and its metabolites in biological fluids, a num6ier of investigators have attempted to correlate acetylator phenotype with the drug's therapeutic and toxic
0306-5251/79/050451-02
b
a CONHNH2
Figure 1
CH2CH2NHNH2
The structural formulae of a) isoniazid and
b) phenelzine.
effects. However, an association between phenotype and response should not necessarily be assumed to demonstrate that phenelzine is metabolized by acetylation, since other factors might be involved in determining the drug's effects. The efficacy of phenelzine as an antidepressant is controversial (Morris & Beck, 1973). Differences in its clinical effects may be due to factors other than interindividual variation in metabolism, and include heterogeneity of depressive illness, wide symptom variation within a diagnostic group, differences in drug trial duration, differences in phenelzine dosage and in methods of assessing the clinical response. The effects of phenelzine have been examined in relation to acetylator status in endogenous and neurotic depressions (Evans et al. 1965), and in various forms of neurotic depression (Davidson, McLeod & Blum, 1978; Davidson, McCleod & White, 1978; Johnstone & Marsh, 1973; Johnstone, 1976; Marshall, Mountjoy, Cambell, Garside, Leitch & Roth, 1978; Tyrer & Gardner, 1978). All studies except that of Johnstone & Marsh (1977) have shown no difference in clinical response between slow and fast acetylators. The latter workers reported significant benefit from the drug only in slow acetylators, whilst fast acetylators respond just as well to placebo. However, the design of their trial was inadequately randomised, and the interpretation of their within-group data may have been distorted by phenelzine 'wash-out' during the placebo period. Carr (1974) challenged the interpretation of these results since some of the data suggests that both phenotypes improved equally well. It is, however, possible that slow acetylators do respond more quickly to phenelzine, and Marshall et al. (1978) have shown a significant treatment effect in slow acetylators after 2 weeks, but by 4 weeks both slow and fast acetylators had improved similarly. One uncontrolled prospective trial of phenelzine has reported a difference in side-effects between slow and fast acetylators (Evans et al., 1965). In this study, side-effects were spontaneously reported and severe effects were found to be significantly increased amongst slow acetylators. However, no other workers have reported any difference in the incidence of side
452
EDITORIAL
effects between the two phenotypes (Davidson, McLeod & Blum, 1978; Johnstone & Marsh, 1973; Johnstone 1976; Marshall et al., 1978). Monoamine oxidase inhibition (MAOI) during phenelzine treatment has been studied in relation to acetylator phenotype using patients' platelets (Davidson, McLeod & Blum 1978; Marshall et al., 1978) and by measuring urinary excretion of 5hydroxy indole acetic acid (Marshall et al., 1978) or urinary tryptamine (Johnstone, 1976), since genetic variation in phenelzine acetylation might be associated with similar variation in MAOI. However, no correlation was established in any study. The dose of administered phenelzine may be more important in determining clinical response than acetylator status. Tyrer & Gardner (1978) reported significantly greater improvement in patients receiving 90 mg phenelzine per day, than those receiving 45 mg
per day. This confirms the findings of Ravaris, Nies, Robinson, Ibes, Lamborns & Korson (1976) who have suggested that for an adequate antidepressant effect the degree of MAOI should exceed 80%. Davidson, McLeod & White (1978) have shown that a 60% reduction of monoamine oxidase activity was required for an adequate therapeutic effect in nondelusional depression. The present evidence does not support therefore either the hypothesis that phenelzine undergoes polymorphic acetylation, or that acetylator phenotype is a determinant of the drug's clinical effects. GILLIAN L. SANDERS & M.D. RAWLINS Wolfson Unit of Clinical Pharmacology, Department of Pharmacological Sciences, Claremont Place, The University, Newcastle upon Tyne.
References CADDY, B., STEAD, A.H. & JOHNSTONE, E.C. (1978). The urinary excretion of phenelzine Br. J. clin. Pharmac., 6, 185-188. CARR, A. (1974). Phenelzine and acetylator status. Lancet, u, 412. DAVIDSON, J., McLEOD, M. & BLUM, M. (1978). Acetylation phenotype, platelet monoamine oxidase inhibition and the effectiveness of phenelzine in depression. Am. J. Psychiat., 135, 467-469. DAVIDSON, J., McLEOD, M. & WHITE, H.(1978). Inhibition of platelet monoamine oxidase in depressed subjects treated with phenelzine.Am.J. Psychiat., 135,470-472.
depressed patients on phenelzine. Psychopharmacology, 46, 289-294. LUNDE, P.K.M., FRISLID, K. & HANSTEEN, V. (1977).
Disease and acetylation polymorphism. Clin. Pharmacokin., 2,182-197. MARSHALL, E.F. (1976). The myth of phenelzine acetylation. Br. med. J., 2, 817. MARSHALL, E.F., MOUNTJOY, C.Q., CAMBELL, I.C.,
GARSIDE, R.F., LEITCH, I.M. & ROTH, M. (1978). The influence of acetylator phenotype on the outcome of treatment with phenelzine in a clinical trial. Br. J. clin. Pharmac., 6, 247-254.
DEVADATTA, S., GANGADHARUM, P.RJ., ANDREWS, R.H., FOX, W., RAMAKRISHNAN, C.V., SELKON, J.B. &
MITCHELL, J.R., THORGEIRRSON, J.P., BLACK, M., TIMBRELL, J.A., SNODGRASS, W.R., POTTER, W.Z.,
VELU, S. (1960). Peripheral neuritis due to isoniazid. Bull. Wld. Hlth. Org., 23, 587. EVANS, D.A.P., MANLEY, K.A. & MCKUSICK, V.A. (1960). Human isoniazid metabolism - a genetically determined phenomenon. Br. med. J., 2, 485-491. EVANS, D.A.P., DAVISON, K. & PRATT, R.T.C. (1965). The influence of acetylator phenotype on the effects of treating depression with phenelzine. Clin. Pharmac. Ther., 6, 430-435. JOHNSTONE, E.C. & MARSH, W. (1973). Acetylator status and response to phenelzine in depressed patients. Lancet, 1, 567-570. JOHNSTONE, E.C. (1976). The relationship between acetylator status and inhibition of monoamine oxidase excretion of free drug and antidepressant response in
JOLLOW, DJ. & KEISER, H.R. (1975). Increased incidence of isoniazid hepatitis in rapid acetylators possible relation to hydrazine metabolites. Clin. Pharmac. Ther., 18, 70. MORRIS, J.F. & BECK, A.T. (1974) The efficacy of antidepressant drugs. Arch. Gen. Psychiat., 30, 667-674. RAVARIS, C.L. NIES, A., ROBINSON, D.S., IBES, J.O., LAMBORNS, K. & KORSON, L. (1976). A multiple dose
controlled study of phenelzine in depression-anxiety states. Arch. Gen. Psychiat., 33, 347-350. TILSTONE, WJ., MARGOT, P. & JOHNSTONE, E.C. (1979) Acetylation of phenelzine. Psychopharmacology, (in press). TYRER, P. & GARDNER, M. (1978). Acetylator status and response to phenelzine. Lancet, I, 994-995.
Br. J. clin. Pharmac. (1979), 7,451-452
PHENELZINE: ACETYLATOR STATUS AND CLINICAL RESPONSE Acetylation is an important route of metabolism and thus drug elimination. More than one enzyme system is involved in acetylation, but N-acetyl transferase has been shown to acetylate a number of aromatic amines including isoniazid, sulphadimidine, sulphapyridine, dapsone, hydrallazine and procainamide (Lund, Frislid & Hansteen, 1977). N-acetyl transferase, though mainly present in the liver, can be found also in the gastrointestinal mucosa and may be present in other tissues. Since phenelzine is a amine, with a chemical structure similar to that of several compounds undergoing acetylation (Figure 1), it has been proposed that it may also undergo metabolism by N-acetyl transferase (Evans, Davison & Pratt, 1965). However, the acetylated derivative of phenelzine, acetyl phenelzine, has yet to be identified as a metabolite in either man or any other animal (Marshall, 1976), and it is only recently that quantitation of phenelzine in urine has been possible. An assay (Caddy, Stead & Johnstone, 1978) which measures the parent compound and certain nonacetylated derivatives, has shown that less than 5% of the drug is excreted in these forms which suggests extensive metabolism. Tilstone, Margot & Johnstone (1979) have suggested from indirect evidence that acetylphenelzine is produced when homogenates of rat and human liver are incubated with phenelzine in vitro. However, their methodology did not include identification or measurement of acetylphenelzine. N-acetyl transferase activity shows genetic variation, and populations can be divided into two phenotypes (fast or slow acetylators) though the ratio varies. Evans Marley & McKusick, (1960) investigated the genetic control of isoniazid metabolism and showed that slow acetylators are autosomal homozygous recessive while fast acetylators are either heterozygous or homozygous dominant. Thus, slow acetylators will have higher plasma concentrations of the parent drug and lower concentrations of the acetylated metabolite: they may therefore show therapeutic responses at lower doses than rapid acetylators. Moreover, slow acetylators will be a greater risk from adverse reactions due to the parent compound (such as isoniazid peripheral neuropathy) (Devadatta, Gangadharum, Andrews, Fox, Ramakrishnan, Selkon & Velu, 1960), whilst rapid acetylators will be at greater risk from adverse reactions due to the acetylated metabolites (such as isoniazid hepatitis) (Mitchell, Thorgeirrsson, Black, Timbrell, Snodgrass, Potter, Jollow & Keiser, 1975). Because of the difficulties in measuring phenelzine and its metabolites in biological fluids, a num6ier of investigators have attempted to correlate acetylator phenotype with the drug's therapeutic and toxic
0306-5251/79/050451-02
b
a CONHNH2
Figure 1
CH2CH2NHNH2
The structural formulae of a) isoniazid and
b) phenelzine.
effects. However, an association between phenotype and response should not necessarily be assumed to demonstrate that phenelzine is metabolized by acetylation, since other factors might be involved in determining the drug's effects. The efficacy of phenelzine as an antidepressant is controversial (Morris & Beck, 1973). Differences in its clinical effects may be due to factors other than interindividual variation in metabolism, and include heterogeneity of depressive illness, wide symptom variation within a diagnostic group, differences in drug trial duration, differences in phenelzine dosage and in methods of assessing the clinical response. The effects of phenelzine have been examined in relation to acetylator status in endogenous and neurotic depressions (Evans et al. 1965), and in various forms of neurotic depression (Davidson, McLeod & Blum, 1978; Davidson, McCleod & White, 1978; Johnstone & Marsh, 1973; Johnstone, 1976; Marshall, Mountjoy, Cambell, Garside, Leitch & Roth, 1978; Tyrer & Gardner, 1978). All studies except that of Johnstone & Marsh (1977) have shown no difference in clinical response between slow and fast acetylators. The latter workers reported significant benefit from the drug only in slow acetylators, whilst fast acetylators respond just as well to placebo. However, the design of their trial was inadequately randomised, and the interpretation of their within-group data may have been distorted by phenelzine 'wash-out' during the placebo period. Carr (1974) challenged the interpretation of these results since some of the data suggests that both phenotypes improved equally well. It is, however, possible that slow acetylators do respond more quickly to phenelzine, and Marshall et al. (1978) have shown a significant treatment effect in slow acetylators after 2 weeks, but by 4 weeks both slow and fast acetylators had improved similarly. One uncontrolled prospective trial of phenelzine has reported a difference in side-effects between slow and fast acetylators (Evans et al., 1965). In this study, side-effects were spontaneously reported and severe effects were found to be significantly increased amongst slow acetylators. However, no other workers have reported any difference in the incidence of side
452
EDITORIAL
effects between the two phenotypes (Davidson, McLeod & Blum, 1978; Johnstone & Marsh, 1973; Johnstone 1976; Marshall et al., 1978). Monoamine oxidase inhibition (MAOI) during phenelzine treatment has been studied in relation to acetylator phenotype using patients' platelets (Davidson, McLeod & Blum 1978; Marshall et al., 1978) and by measuring urinary excretion of 5hydroxy indole acetic acid (Marshall et al., 1978) or urinary tryptamine (Johnstone, 1976), since genetic variation in phenelzine acetylation might be associated with similar variation in MAOI. However, no correlation was established in any study. The dose of administered phenelzine may be more important in determining clinical response than acetylator status. Tyrer & Gardner (1978) reported significantly greater improvement in patients receiving 90 mg phenelzine per day, than those receiving 45 mg
per day. This confirms the findings of Ravaris, Nies, Robinson, Ibes, Lamborns & Korson (1976) who have suggested that for an adequate antidepressant effect the degree of MAOI should exceed 80%. Davidson, McLeod & White (1978) have shown that a 60% reduction of monoamine oxidase activity was required for an adequate therapeutic effect in nondelusional depression. The present evidence does not support therefore either the hypothesis that phenelzine undergoes polymorphic acetylation, or that acetylator phenotype is a determinant of the drug's clinical effects. GILLIAN L. SANDERS & M.D. RAWLINS Wolfson Unit of Clinical Pharmacology, Department of Pharmacological Sciences, Claremont Place, The University, Newcastle upon Tyne.
References CADDY, B., STEAD, A.H. & JOHNSTONE, E.C. (1978). The urinary excretion of phenelzine Br. J. clin. Pharmac., 6, 185-188. CARR, A. (1974). Phenelzine and acetylator status. Lancet, u, 412. DAVIDSON, J., McLEOD, M. & BLUM, M. (1978). Acetylation phenotype, platelet monoamine oxidase inhibition and the effectiveness of phenelzine in depression. Am. J. Psychiat., 135, 467-469. DAVIDSON, J., McLEOD, M. & WHITE, H.(1978). Inhibition of platelet monoamine oxidase in depressed subjects treated with phenelzine.Am.J. Psychiat., 135,470-472.
depressed patients on phenelzine. Psychopharmacology, 46, 289-294. LUNDE, P.K.M., FRISLID, K. & HANSTEEN, V. (1977).
Disease and acetylation polymorphism. Clin. Pharmacokin., 2,182-197. MARSHALL, E.F. (1976). The myth of phenelzine acetylation. Br. med. J., 2, 817. MARSHALL, E.F., MOUNTJOY, C.Q., CAMBELL, I.C.,
GARSIDE, R.F., LEITCH, I.M. & ROTH, M. (1978). The influence of acetylator phenotype on the outcome of treatment with phenelzine in a clinical trial. Br. J. clin. Pharmac., 6, 247-254.
DEVADATTA, S., GANGADHARUM, P.RJ., ANDREWS, R.H., FOX, W., RAMAKRISHNAN, C.V., SELKON, J.B. &
MITCHELL, J.R., THORGEIRRSON, J.P., BLACK, M., TIMBRELL, J.A., SNODGRASS, W.R., POTTER, W.Z.,
VELU, S. (1960). Peripheral neuritis due to isoniazid. Bull. Wld. Hlth. Org., 23, 587. EVANS, D.A.P., MANLEY, K.A. & MCKUSICK, V.A. (1960). Human isoniazid metabolism - a genetically determined phenomenon. Br. med. J., 2, 485-491. EVANS, D.A.P., DAVISON, K. & PRATT, R.T.C. (1965). The influence of acetylator phenotype on the effects of treating depression with phenelzine. Clin. Pharmac. Ther., 6, 430-435. JOHNSTONE, E.C. & MARSH, W. (1973). Acetylator status and response to phenelzine in depressed patients. Lancet, 1, 567-570. JOHNSTONE, E.C. (1976). The relationship between acetylator status and inhibition of monoamine oxidase excretion of free drug and antidepressant response in
JOLLOW, DJ. & KEISER, H.R. (1975). Increased incidence of isoniazid hepatitis in rapid acetylators possible relation to hydrazine metabolites. Clin. Pharmac. Ther., 18, 70. MORRIS, J.F. & BECK, A.T. (1974) The efficacy of antidepressant drugs. Arch. Gen. Psychiat., 30, 667-674. RAVARIS, C.L. NIES, A., ROBINSON, D.S., IBES, J.O., LAMBORNS, K. & KORSON, L. (1976). A multiple dose
controlled study of phenelzine in depression-anxiety states. Arch. Gen. Psychiat., 33, 347-350. TILSTONE, WJ., MARGOT, P. & JOHNSTONE, E.C. (1979) Acetylation of phenelzine. Psychopharmacology, (in press). TYRER, P. & GARDNER, M. (1978). Acetylator status and response to phenelzine. Lancet, I, 994-995.
