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THE PHARMACOKINETICS OF TRICYCLIC ANTIDEPRESSANT DRUGS IN THE ELDERLY M . FURLANUT and P. BENETELLO Department of Pharmacology and Institute of Neurology, University of Padua, Italy Received in final form 13 June 1989
SUMMARY Antidepressants, especially tricyclic agents (TCAs), are increasingly used in geriatric patients since depression is a common mood disorder in the elderly and the size of elderly population is increasing . Notwithstanding the importance of kinetics to better use of drugs, its study in the elderly (regarding WAS) is not sufficiently developed . The present paper briefly reviews the available data on amitriptyline, nortriptyline, protriptyline, imipramine, desipramine and clomipramine kinetics in the elderly. KEY WORDS :
elderly, tricyclic antidepressants, kinetics . INTRODUCTION
Among mood disorders depression is very frequent in the aged and antidepressants, especially tricyclic derivatives (TCAs), are commonly used against these disturbances [1, 2] . Side effects of WAS are reported to be common in the elderly [3-5] . They may be due both to age-related changes in sensitivity, to drug receptors and to kinetic variations in aged subjects [6-10] . Surprisingly, in spite of the relevance of pharmacokinetics for a rational use of drugs in humans [ 11 ], systematic studies on TCA kinetics are scarce in aged patients . The present paper reviews the available data on kinetics of currently used TCAs (amitriptyline, nortriptyline, protriptyline, imipramine, desipramine, clomipramine) . Their structural formulae are presented in Fig . 1 .
BIOAVAILABILITY TCAs are usually administered by oral route . In spite of the high solubility in lipids, their oral bioavailability is low (about 20-70%) when compared with parenteral routes because of a remarkable first pass effect [12-17] . Theoretically, a reduced first pass effect, in relation to a decrease of hepatic clearance for age, might improve oral bioavailability of TCAs in the elderly . However, the meagre data at our disposal do not allow us to confirm this hypothesis . On the contrary, the studies 1043-6618/90/010015-11/$03 .00/0
© 1990 The Italian Pharmacological Society
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II
R'
RI CH 2 -CHZ CH 2 N\
CH-CH -CH N\ 2 2 R2 Amitriptyline R'=CH 3 Nrrtriptyline R' =H
R2
R 2 =CH 3
Protriptyline
R' =H
R 2 =CH 3
R2 =CH 3
R5
I
Imipramine R3 =CH 3
/R3
Desipramine
4 R =CH 3
R3 =H R 4 =CH 3
R 5 =H
RS=H
CH -CH2CH2 N \R
4
Chlorimipramine R 3 =CH3
R 4 =CH 3
RS=CL
Fig . 1 . Structural formulae of amitriptyline, nortriptyline, protriptyline, imipramine, desipramine and clomipramine (chlorimipramine).
performed until now were not able to demonstrate any variation on bioavailability of amitriptyline and imipramine in aged people [18, 19]. Often, aged patients are in politherapy and TCA interactions with other drugs [20-22], or with alcohol [23], and smoke [10, 24] might modify oral bioavailability . To our knowledge, no studies have been performed in the elderly to elucidate this point .
DISTRIBUTION TCAs are very lipophilic substances and are highly bound to plasma proteins (over 90%) especially to albumin, at -acid glycoprotein and lipoproteins [25-28] . Since only free drug is diffusible, variations in plasma protein binding may affect TCA distribution and their concentration at receptor sites, thus conditioning the antidepressant response . Therefore, drug interactions and variations in plasma protein concentrations may play an important role in determining individual variations of the pharmacological effects of TCAs . The elderly are often in polytherapy and may have, with respect to younger ones, a lower content of plasma proteins [9]. It was demonstrated that imipramine binding to lipoproteins is higher in hyperlipoproteinaemic than in normal subjects [29] . Ageing may promote an increase of a t-acid glycoprotein and lipoproteins, so, probably, inducing variations on TCA distribution . Similarly, drugs affecting lipoprotein plasma concentrations may induce modifications on TCA distribution . At present, however, the data at our disposal on TCA protein binding in the elderly are conflicting [30] . Recently it was demonstrated that no relationship exists between age and imipramine binding despite the increase of a t -acid glycoprotein concentration observed in the aged patients studied [31] . Among the factors conditioning TCA distribution, tissue composition is the most important one . Generally speaking, TCA volume of distribution (V,) would be higher in the elderly
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than in youth due to a decrease of body water content and an increase of fat composition . However, while amitriptyline V was demonstrated to be higher in geriatric patients [18], a similar relationship was not shown for imipramine [19, 32] .
METABOLISM TCA metabolism is extensive and complex. It involves demethylation and hydroxylation reactions (Fig. 2) . Hydroxymetabolites are subsequently conjugated with glucuronic acid . Amitriptyline is metabolized chiefly via N-demethylation to Imipramine (IMI)
I
IH3
CH z-CH2CH2N CH,
Desipramine (DMI)
H I
CH 2 -CH zCHZ-Î CH Z
I
1 CH3 2-OH-IMI-glucuronide
Fig . 2 .
2-OH-IMI-glucuronide
Major metabolic pathways of imipramine as example of TCAs biotransformation in humans .
form 10-OH-amitriptyline or by a combination of these reactions to generate 10OH-nortriptyline [33] . The major metabolite of nortriptyline is the l0-hydroxy derivative [34]. Both 10-OH-amitriptyline and 10-OH-nortriptyline may be present and in cis or in trans form. Imipramine biotransformation involves demethylation to desipramine and or hydroxylation in position 2 to form 2-OH-imipramine and 2OH-desipramine . 2-OH-Desipramine represents the main metabolite of desipramine [35-37] . Desmethyl-clomipramine and the 8-hydroxy derivatives of both clomipramine and desmethyl-clomipramine are the principal metabolites of clomipramine [38] . While unconjugated hydroxymetabolites of TCAs exert pharmacological effects (in vitro and in animals) similar to those observed with parent drugs [39-43], their clinical effect in man has not been definitely established .
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One clinical study, however, reported a possible antidepressant activity of 2-OHdesipramine [44]; a second one suggested (in children) an antienuretic effect correlating better with total plasma levels (imipramine + desipramine + 2-OHmetabolites) than with parent compounds only [45] (we were not able to confirm this report [46]) ; finally, a third report suggested that in depressed patients treated with nortriptyline, the 10-OH metabolite may play an important clinical role since the ratio between the concentration of the parent compound to metabolite in CSF correlated significantly with the amelioration score [47] . A large interindividual variability was demonstrated in TCA biotransformation . Drug interactions [20-22, 48], alcohol and smoking [10, 23, 24] may contribute to this variability. Furthermore, biotransformation of TCAs may be complicated by a non-linear kinetics since there was demonstrated a disproportionate increase of imipramine and desipramine serum concentrations after the administered dose was increased [49, 50] . Dose-dependent kinetics for imipramine are reported also in the elderly [51 ]. There is evidence that the hepatic metabolism of various drugs is reduced as age increases [9] . However, findings for TCAs are scarce and conflicting . Some studies [3, 10, 52] demonstrated that older patients show higher steady-state plasma concentrations of amitriptyline, imipramine, clomipramine and desmethylclomipramine with respect to younger ones . Older age and female gender were associated with higher plasma levels of amitriptyline [52] . In contrast with these findings, no relationship between amitriptyline and nortriptyline plasma levels and age and gender was demonstrated in another study [24] . Similarly, Schultz et al. [18] in an investigation on amitriptyline disposition concluded that the differences seen between young and elderly on plasma half-lives were due to an increase of Vd rather than a decrease of systemic clearance . Recently, we conducted a kinetic study on imipramine in 26 depressed patients requiring TCAs . Whereas a clear relationship between age and serum half-life and total body clearance was demonstrated, a similar relationship was lacking between age and Vd [32] . These results confirm a previous report [19] on imipramine disposition in healthy elderly subjects in which, however, hydroxymetabolites were not determined . Imipramine metabolite determination in our study suggested that demethylation instead of hydroxylation is compromised as age increases since only imipramine/desipramine ratios differ significantly in young and older patients . In fact, imipramine/OHimipramine and desipramine/OH-desipramine ratios did not differ significantly between the two age classes studied .
RENAL EXCRETION Small amounts of TCAs are excreted as parent compound in the urine . Most (over 90%) imipramine and desipramine is eliminated in the urine especially as conjugated derivatives [33, 34, 53, 54] . Probably, glomerular filtration does not represent the unique means of renal excretion but also tubular active transport may be important since 2-OH-desipramine clearance is higher than creatinine clearance [55] . Conjugated metabolites show a lower renal clearance than free ones [56] . Renal failure produces no alterations on TCA metabolism but an increase on
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hydroxymetabolite retention especially conjugated ones [57, 58] . In anuric patients, conjugated metabolites in plasma may vary from 500% to 1500% [59] and from 1000% to 2000% [57] in respect of the values found in controls with normal renal function . Although they are believed to be pharmacologically inert, hydrolysis in the gut and reabsorption, and inhibition of metabolism of parent compounds were reported as possible clinical consequences of this accumulation [60] . A diminished renal function is commonly observed in elderly people . In man, renal flow decreases at a rate of about 1 . 9% per year inversely with age [61] . Glomerular filtration declines approximately by 35% between 20 and 90 years of age [62] . This represents the explanation for OH TCA metabolite accumulation in the blood of elderly depressed patients . Renal clearance of OH-desipramine was demonstrated to be impaired in these patients [63] . Young et al. [64] in a study on steady-state plasma concentrations of nortriptyline and its hydroxy-unconjugated metabolite, demonstrated that elderly patients developed higher OH-metabolite levels than younger ones . They noted a positive, even if low, correlation between plasma OH-metabolite/parent compound ratios and creatinine serum concentrations. In contrast, Schultz et al. [18] did not demonstrate significant differences in plasma AUC 10-OH-amitriptyline/AUC amitriptyline ratio between young and elderly subjects . However, the study was carried out to investigate single oral and i .v. kinetics of amitriptyline . No multiple dosing was studied. Furthermore, the number of patients was probably not enough since standard deviation of AUC ratio of 10-OH-metabolite amitriptyline in young (seven subjects) was ±66 .66% from the mean whereas in the elderly (five subjects) it was ±41 . 66%. Unfortunately, no other studies, to our knowledge, were performed on renal clearance of OH-metabolites of TCAs in the elderly .
MONITORING OF BLOOD CONCENTRATIONS Monitoring of blood concentrations may be in some circumstances a useful tool for a rational drug therapy. Concerning TCAs, it has been suggested that plasma concentration guided therapy of depression in individual patients may result in better results [65] . In fact, steady-state plasma levels of TCAs in individual patients treated with equal per kg body weight oral doses may have a 36-fold variation [66]. Measurements of blood TCAs and their metabolites are now easy to perform since specific, sensitive and relatively inexpensive methods are at our disposal [67-72] (for a review of gas chromatography methods see Van Brunt [73]) . They permit the quantification of parent compounds and various metabolites in order to study a relationship between blood concentrations and therapeutic and/or toxic effects . Notwithstanding this technical improvement, no general agreement exists on the utility of measurement of TCA levels in blood [74]. With imipramine, a minimum of 120 ng/ml of plasma of parent compound plus desipramine is needed for a therapeutic effect [75, 76] . Probably the concentration decided should not be lower than 240 ng/ml [77] . No agreement is found in the psychiatric literature on the therapeutic concentrations of desipramine [78, 79] and amitriptyline [80, 811 . However, some investigators suggest a therapeutic range for amitriptyline (parent compound plus nortriptyline) of 120-250 ng/ml [82-84] . For nortriptyline, a
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curvilinear relationship between plasma concentrations and clinical response is reported in the majority of studies with a therapeutic window at 50-150 ng/ml [85-88] . As for protriptyline and clomipramine, the results are inconclusive [89-91] . In spite of the suggested clinical [44-45,47] and toxicological [92,931 activity of unconjugated OH-metabolites of TCAs, the utility of monitoring these substances is largely hypothetical [94-97] . Among the indications to monitor TCA plasma levels, age is probably one of the most important elements due to the sensitivity to adverse effects of these drugs in the elderly . Furthermore, aged people risk drug interactions since they often are in polytherapy and at risk of dangerous cardiovascular effects [98] . In spite of the very few studies on monitoring plasma levels among the elderly, no substantial differences seem to be found in these reports compared to previous studies in younger patients [99-102] . If these levels can be accepted also for old people, it might be useful to know the dosage which enables these levels to be reached . This goal can sometimes be obtained by calculating the daily dose on the basis of kinetic parameters obtained by means of single dose kinetics in patients to be treated [103, 104] .
CONCLUSIONS TCA administration in geriatric patients is an increasing problem since depression is a common disturbance in the elderly and the size of the elderly world population is increasing. Therefore, a precise knowledge on kinetics in this age group is required . The limited available data seem to confirm the assumption that metabolism represents a crucial point in drug elimination from the body during old age. Unfortunately, only a few specific studies were performed on TCA kinetics in the elderly . However, this is a common feature in clinical psychopharmacology since geriatrics is a field of study which is now attracting more attention .
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79. Nelson JC, Jatlow P, Quinlan DM, Bowers MB . Desipramine plasma concentration and antidepressant response. Am J Psychiat 1982; 39: 1419-22 . 80 . Coppen A, Montgomery S, Ghose K, et al. Amitriptyline plasma-concentration and clinical effect . A World Health Organization collaborative study . Lancet 1978 ; is 63-6 . 81 . Jungkunz G, Kuss HJ . Amitriptyline and its demethylation rate . Lancet 1978 ; ii : 1263-4 . 82 . Braithwaite RA, Goulding R, Theano G, Bailey J, Coppen A . Plasma concentration of amitriptyline and clinical response. Lancet 1972 ; is 1297-300 . 83 . Ziegler VE, Co BT, Taylor JR, Clayton PJ, Biggs JT . Amitriptyline plasma levels and therapeutic response . Clin Pharmacol Ther 1976 ; 19 : 795-801 . 84 . Kupfer DJ, Hamin 1, Spiker DG, Grau T, Coble P. Amttptyline plasma levels and clinical response in primary depression . Clin Pharmacol Ther 1977 ; 22 : 904-11 . 85 . Montgomery S, Braithwaite RA, Crammer JL . Routine nortriptyline levels in the treatment of depression. Br Med J 1977 ; 3 : 166-7 . 86 . Kragh-Serensen P, Hansen CE, Baastrup PC, Hvidberg EF . Self-inhibiting action of nortriptyline's antidepressive effect at high plasma levels . Psychopharmacologia 1976 ; 45: 305-16 . 87 . Ziegler VE, Clayton PS, Taylor JR, Co BT. Nortriptyline plasma levels and therapeutic response. Clin Pharmacol Ther 1976; 20 : 458-63 . 88 . Montgomery S, Braithwaite R, Dawling S, McAuley R . High plasma nortriptyline levels in the treatment of depression. Clin Pharmacol Ther 1978 ; 23-.309-14 . 89 . Biggs JT, Ziegler VE. Protriptyline plasma levels and antidepressant response . Clin Pharmacol Ther 1977 ; 22: 269-73 . 90 . Träskman Lil, Asberg M, Bertilsson L, et al. Plasma levels of chlorimipramine and its metabolite during treatment of depression . Clin Pharmacol Ther 1979 ; 26 : 600-10 . 91 . Vandel B, Vandel S, Jounet JM, Allers G, Volniat R . Relationship between the plasma concentration of clomipramine and desmethylciomipramine in depressive patients and the clinical response . EurJ Clin Pharmacol 1982 ; 22 : 15-20 . 92. Kutcher SP, Reid K, Dubbin JD, Shulman KI . Electrocardiogram changes and therapeutic desipramine and 2-hydroxy-desipramine concentrations in elderly depressives . BrJPsychiat 1986 ; 148 : 676-9 . 93 . Young RC, Alexopoulos GS, Shamoian CA, Dhar AK, Kutt H . Plasma 10hydroxynortriptyline and ECG changes in elderly depressed patients . Am J Psychiat 1985 ;142:866-8. 94 . Linoila M, Insel T, Kilts C, Potter WZ, Murphy DL . Plasma steady-state concentrations of hydroxylated metabolites of clomipramine . Clin Pharmacol Ther 1982 ; 32 : 208-11 . 95 . Nelson JC, Bock JL, Jatlow PI . Clinical implication of 2-hydroxydesipramine plasma concentrations . Clin Pharmacol Ther 1983 ; 33 : 183-9 . 96 . Amsterdam JD, Brunswick DJ, Potter L, Winokur A, Rickels K . Desipramine and 2hydroxydesipramine plasma levels in endogenous depressed patients . Lack of correlation with therapeutic response . Arch Gen Psychiat 1985 ; 42 : 361-4 . 97 . Kutcher SP, Shulman KI, Reed K . Desipramine plasma concentrations and therapeutic response in elderly depressives : a naturalistic pilot study. Can J Psychiat 1986 ; 31 : 752-4 . 98 . Glasman A, Carino JS, Roose SP . Adverse effects of tricyclic antidepressants : focus on the elderly. In : Usdin E, Asberg M, Bertilsson F, Sjögvist F, eds . Frontiers in biochemical and pharmacological research in depression . New York: Raven Press, 1984 : 391-8 . 99 . Smith RC, Reed K, Leelavathi DE . Pharmacokinetics and the effects of nortriptyline in geriatric depressed patients . Psychopharmacol Bull 1980 ; 16 : 54-7 . 100 . Cutler NR, Zavadil AP, Eisdorfer C, Ross R, Potter WZ. Concentrations of desipramine in elderly women . Am J Psychiat 1981 ; 138 : 1235-7 . 101 . Nelson JC, Jatlow PI, Mature C . Desipramine plasma levels and response in elderly melancholic patients . J Clin Psychopharmacol 1985 ; 5 : 217-20 . 102 . Kumar V, Smith RC, Reed K, Leelavathi DE, Plasma levels and effects of nortriptyline in geriatric depressed patients. Acta Psychiatr Scand 1987 ; 75 : 20-8 .
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103 . Dawling S, Crome P, Braithwaite RA, Lewis RR . Nortriptyline therapy in elderly patients : dosage prediction after single dose pharmacokinetic study. Eur J Clin Pharmacol1980 ; 18 : 147-50. 104 . Schneider LS, Cooper TB, Staples FR, Sloane RB . Prediction of individual dosage of nortriptyline in depressed elderly outpatients . J Clin Psychopharmacol 1987 ; 7 : 311-14 .
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THE PHARMACOKINETICS OF TRICYCLIC ANTIDEPRESSANT DRUGS IN THE ELDERLY M . FURLANUT and P. BENETELLO Department of Pharmacology and Institute of Neurology, University of Padua, Italy Received in final form 13 June 1989
SUMMARY Antidepressants, especially tricyclic agents (TCAs), are increasingly used in geriatric patients since depression is a common mood disorder in the elderly and the size of elderly population is increasing . Notwithstanding the importance of kinetics to better use of drugs, its study in the elderly (regarding WAS) is not sufficiently developed . The present paper briefly reviews the available data on amitriptyline, nortriptyline, protriptyline, imipramine, desipramine and clomipramine kinetics in the elderly. KEY WORDS :
elderly, tricyclic antidepressants, kinetics . INTRODUCTION
Among mood disorders depression is very frequent in the aged and antidepressants, especially tricyclic derivatives (TCAs), are commonly used against these disturbances [1, 2] . Side effects of WAS are reported to be common in the elderly [3-5] . They may be due both to age-related changes in sensitivity, to drug receptors and to kinetic variations in aged subjects [6-10] . Surprisingly, in spite of the relevance of pharmacokinetics for a rational use of drugs in humans [ 11 ], systematic studies on TCA kinetics are scarce in aged patients . The present paper reviews the available data on kinetics of currently used TCAs (amitriptyline, nortriptyline, protriptyline, imipramine, desipramine, clomipramine) . Their structural formulae are presented in Fig . 1 .
BIOAVAILABILITY TCAs are usually administered by oral route . In spite of the high solubility in lipids, their oral bioavailability is low (about 20-70%) when compared with parenteral routes because of a remarkable first pass effect [12-17] . Theoretically, a reduced first pass effect, in relation to a decrease of hepatic clearance for age, might improve oral bioavailability of TCAs in the elderly . However, the meagre data at our disposal do not allow us to confirm this hypothesis . On the contrary, the studies 1043-6618/90/010015-11/$03 .00/0
© 1990 The Italian Pharmacological Society
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II
R'
RI CH 2 -CHZ CH 2 N\
CH-CH -CH N\ 2 2 R2 Amitriptyline R'=CH 3 Nrrtriptyline R' =H
R2
R 2 =CH 3
Protriptyline
R' =H
R 2 =CH 3
R2 =CH 3
R5
I
Imipramine R3 =CH 3
/R3
Desipramine
4 R =CH 3
R3 =H R 4 =CH 3
R 5 =H
RS=H
CH -CH2CH2 N \R
4
Chlorimipramine R 3 =CH3
R 4 =CH 3
RS=CL
Fig . 1 . Structural formulae of amitriptyline, nortriptyline, protriptyline, imipramine, desipramine and clomipramine (chlorimipramine).
performed until now were not able to demonstrate any variation on bioavailability of amitriptyline and imipramine in aged people [18, 19]. Often, aged patients are in politherapy and TCA interactions with other drugs [20-22], or with alcohol [23], and smoke [10, 24] might modify oral bioavailability . To our knowledge, no studies have been performed in the elderly to elucidate this point .
DISTRIBUTION TCAs are very lipophilic substances and are highly bound to plasma proteins (over 90%) especially to albumin, at -acid glycoprotein and lipoproteins [25-28] . Since only free drug is diffusible, variations in plasma protein binding may affect TCA distribution and their concentration at receptor sites, thus conditioning the antidepressant response . Therefore, drug interactions and variations in plasma protein concentrations may play an important role in determining individual variations of the pharmacological effects of TCAs . The elderly are often in polytherapy and may have, with respect to younger ones, a lower content of plasma proteins [9]. It was demonstrated that imipramine binding to lipoproteins is higher in hyperlipoproteinaemic than in normal subjects [29] . Ageing may promote an increase of a t-acid glycoprotein and lipoproteins, so, probably, inducing variations on TCA distribution . Similarly, drugs affecting lipoprotein plasma concentrations may induce modifications on TCA distribution . At present, however, the data at our disposal on TCA protein binding in the elderly are conflicting [30] . Recently it was demonstrated that no relationship exists between age and imipramine binding despite the increase of a t -acid glycoprotein concentration observed in the aged patients studied [31] . Among the factors conditioning TCA distribution, tissue composition is the most important one . Generally speaking, TCA volume of distribution (V,) would be higher in the elderly
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than in youth due to a decrease of body water content and an increase of fat composition . However, while amitriptyline V was demonstrated to be higher in geriatric patients [18], a similar relationship was not shown for imipramine [19, 32] .
METABOLISM TCA metabolism is extensive and complex. It involves demethylation and hydroxylation reactions (Fig. 2) . Hydroxymetabolites are subsequently conjugated with glucuronic acid . Amitriptyline is metabolized chiefly via N-demethylation to Imipramine (IMI)
I
IH3
CH z-CH2CH2N CH,
Desipramine (DMI)
H I
CH 2 -CH zCHZ-Î CH Z
I
1 CH3 2-OH-IMI-glucuronide
Fig . 2 .
2-OH-IMI-glucuronide
Major metabolic pathways of imipramine as example of TCAs biotransformation in humans .
form 10-OH-amitriptyline or by a combination of these reactions to generate 10OH-nortriptyline [33] . The major metabolite of nortriptyline is the l0-hydroxy derivative [34]. Both 10-OH-amitriptyline and 10-OH-nortriptyline may be present and in cis or in trans form. Imipramine biotransformation involves demethylation to desipramine and or hydroxylation in position 2 to form 2-OH-imipramine and 2OH-desipramine . 2-OH-Desipramine represents the main metabolite of desipramine [35-37] . Desmethyl-clomipramine and the 8-hydroxy derivatives of both clomipramine and desmethyl-clomipramine are the principal metabolites of clomipramine [38] . While unconjugated hydroxymetabolites of TCAs exert pharmacological effects (in vitro and in animals) similar to those observed with parent drugs [39-43], their clinical effect in man has not been definitely established .
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One clinical study, however, reported a possible antidepressant activity of 2-OHdesipramine [44]; a second one suggested (in children) an antienuretic effect correlating better with total plasma levels (imipramine + desipramine + 2-OHmetabolites) than with parent compounds only [45] (we were not able to confirm this report [46]) ; finally, a third report suggested that in depressed patients treated with nortriptyline, the 10-OH metabolite may play an important clinical role since the ratio between the concentration of the parent compound to metabolite in CSF correlated significantly with the amelioration score [47] . A large interindividual variability was demonstrated in TCA biotransformation . Drug interactions [20-22, 48], alcohol and smoking [10, 23, 24] may contribute to this variability. Furthermore, biotransformation of TCAs may be complicated by a non-linear kinetics since there was demonstrated a disproportionate increase of imipramine and desipramine serum concentrations after the administered dose was increased [49, 50] . Dose-dependent kinetics for imipramine are reported also in the elderly [51 ]. There is evidence that the hepatic metabolism of various drugs is reduced as age increases [9] . However, findings for TCAs are scarce and conflicting . Some studies [3, 10, 52] demonstrated that older patients show higher steady-state plasma concentrations of amitriptyline, imipramine, clomipramine and desmethylclomipramine with respect to younger ones . Older age and female gender were associated with higher plasma levels of amitriptyline [52] . In contrast with these findings, no relationship between amitriptyline and nortriptyline plasma levels and age and gender was demonstrated in another study [24] . Similarly, Schultz et al. [18] in an investigation on amitriptyline disposition concluded that the differences seen between young and elderly on plasma half-lives were due to an increase of Vd rather than a decrease of systemic clearance . Recently, we conducted a kinetic study on imipramine in 26 depressed patients requiring TCAs . Whereas a clear relationship between age and serum half-life and total body clearance was demonstrated, a similar relationship was lacking between age and Vd [32] . These results confirm a previous report [19] on imipramine disposition in healthy elderly subjects in which, however, hydroxymetabolites were not determined . Imipramine metabolite determination in our study suggested that demethylation instead of hydroxylation is compromised as age increases since only imipramine/desipramine ratios differ significantly in young and older patients . In fact, imipramine/OHimipramine and desipramine/OH-desipramine ratios did not differ significantly between the two age classes studied .
RENAL EXCRETION Small amounts of TCAs are excreted as parent compound in the urine . Most (over 90%) imipramine and desipramine is eliminated in the urine especially as conjugated derivatives [33, 34, 53, 54] . Probably, glomerular filtration does not represent the unique means of renal excretion but also tubular active transport may be important since 2-OH-desipramine clearance is higher than creatinine clearance [55] . Conjugated metabolites show a lower renal clearance than free ones [56] . Renal failure produces no alterations on TCA metabolism but an increase on
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hydroxymetabolite retention especially conjugated ones [57, 58] . In anuric patients, conjugated metabolites in plasma may vary from 500% to 1500% [59] and from 1000% to 2000% [57] in respect of the values found in controls with normal renal function . Although they are believed to be pharmacologically inert, hydrolysis in the gut and reabsorption, and inhibition of metabolism of parent compounds were reported as possible clinical consequences of this accumulation [60] . A diminished renal function is commonly observed in elderly people . In man, renal flow decreases at a rate of about 1 . 9% per year inversely with age [61] . Glomerular filtration declines approximately by 35% between 20 and 90 years of age [62] . This represents the explanation for OH TCA metabolite accumulation in the blood of elderly depressed patients . Renal clearance of OH-desipramine was demonstrated to be impaired in these patients [63] . Young et al. [64] in a study on steady-state plasma concentrations of nortriptyline and its hydroxy-unconjugated metabolite, demonstrated that elderly patients developed higher OH-metabolite levels than younger ones . They noted a positive, even if low, correlation between plasma OH-metabolite/parent compound ratios and creatinine serum concentrations. In contrast, Schultz et al. [18] did not demonstrate significant differences in plasma AUC 10-OH-amitriptyline/AUC amitriptyline ratio between young and elderly subjects . However, the study was carried out to investigate single oral and i .v. kinetics of amitriptyline . No multiple dosing was studied. Furthermore, the number of patients was probably not enough since standard deviation of AUC ratio of 10-OH-metabolite amitriptyline in young (seven subjects) was ±66 .66% from the mean whereas in the elderly (five subjects) it was ±41 . 66%. Unfortunately, no other studies, to our knowledge, were performed on renal clearance of OH-metabolites of TCAs in the elderly .
MONITORING OF BLOOD CONCENTRATIONS Monitoring of blood concentrations may be in some circumstances a useful tool for a rational drug therapy. Concerning TCAs, it has been suggested that plasma concentration guided therapy of depression in individual patients may result in better results [65] . In fact, steady-state plasma levels of TCAs in individual patients treated with equal per kg body weight oral doses may have a 36-fold variation [66]. Measurements of blood TCAs and their metabolites are now easy to perform since specific, sensitive and relatively inexpensive methods are at our disposal [67-72] (for a review of gas chromatography methods see Van Brunt [73]) . They permit the quantification of parent compounds and various metabolites in order to study a relationship between blood concentrations and therapeutic and/or toxic effects . Notwithstanding this technical improvement, no general agreement exists on the utility of measurement of TCA levels in blood [74]. With imipramine, a minimum of 120 ng/ml of plasma of parent compound plus desipramine is needed for a therapeutic effect [75, 76] . Probably the concentration decided should not be lower than 240 ng/ml [77] . No agreement is found in the psychiatric literature on the therapeutic concentrations of desipramine [78, 79] and amitriptyline [80, 811 . However, some investigators suggest a therapeutic range for amitriptyline (parent compound plus nortriptyline) of 120-250 ng/ml [82-84] . For nortriptyline, a
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curvilinear relationship between plasma concentrations and clinical response is reported in the majority of studies with a therapeutic window at 50-150 ng/ml [85-88] . As for protriptyline and clomipramine, the results are inconclusive [89-91] . In spite of the suggested clinical [44-45,47] and toxicological [92,931 activity of unconjugated OH-metabolites of TCAs, the utility of monitoring these substances is largely hypothetical [94-97] . Among the indications to monitor TCA plasma levels, age is probably one of the most important elements due to the sensitivity to adverse effects of these drugs in the elderly . Furthermore, aged people risk drug interactions since they often are in polytherapy and at risk of dangerous cardiovascular effects [98] . In spite of the very few studies on monitoring plasma levels among the elderly, no substantial differences seem to be found in these reports compared to previous studies in younger patients [99-102] . If these levels can be accepted also for old people, it might be useful to know the dosage which enables these levels to be reached . This goal can sometimes be obtained by calculating the daily dose on the basis of kinetic parameters obtained by means of single dose kinetics in patients to be treated [103, 104] .
CONCLUSIONS TCA administration in geriatric patients is an increasing problem since depression is a common disturbance in the elderly and the size of the elderly world population is increasing. Therefore, a precise knowledge on kinetics in this age group is required . The limited available data seem to confirm the assumption that metabolism represents a crucial point in drug elimination from the body during old age. Unfortunately, only a few specific studies were performed on TCA kinetics in the elderly . However, this is a common feature in clinical psychopharmacology since geriatrics is a field of study which is now attracting more attention .
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35 . Nagy A, Treiber L . Quantitative determination of imipramine and desipramine in human blood plasma by direct densitometry of thin-layer chromatograms . J Pharm Pharmacol 1973 ; 25 : 599-603 . 36 . Suftin TA, DeVane CL, Jusko WJ . The analysis and disposition of imipramine and its active metabolites in man . Psychopharmacology 1984 ; 82 : 310-17 . 37 . Devane CL, Savett M, Jusko WJ. Desipramine and 2-hydroxy-desipramine pharmacokinetics in normal volunteers. EurJClin Pharmacol 1981 ;19 :61-4. 38 . Luskombe DK . Pharmacokinetics of clomipramine . Br J Clin Pract 1979 ; Suppl 3 : 35-50 . 39 . Heikkila RE, Goldfinger SS, Orslansky H . The effect of various phenothiazines and tricyclic antidepresants on the accumulation and relapse of )`Hlnorepinephrine and [ ; H]5-hydroxytryptamine in slice of rat occipital cortex . Res Commun Pathol Pharmacol 1976 ; 13 : 237-50 . 40 . Bertilsson L, Mellstron B, Sjögvist F. Pronounced inhibition of noradrenaline uptake by 10-hydroxymetabolites of nortriptyline . Life Sci 1979 ; 25 : 1285-92 . 41 . Javaid JI, Perel JM, Davis JM . Inhibition of biogenic amines uptake by imipramine, desipramine, 2-OH-imipramine and 2-OH-desipramine in rat brain . Life Sci 1979 ; 24 : 21-8 . 42 . Jandhyala BS, Steenberg ML, Perel JM, Manian AA, Buckley JP . Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of the anesthetized dogs . EurJ Clin Pharmacol 1977 ; 42: 403-10 . 43 . Potter WZ, Calil HM, Manian AA, Zavadil AP, Goodwin FR . Hydroxylated metabolites of tricyclic antidepressants : preclinical assessment of activity . Biol Psychiatr 1979 ; 14 : 601-13 . 44 . Potter WZ, Calil HM, Zavadil AP, et al. Steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in patients : Relationship to clinical effect . Psychopharmacol Bull 1980 ; 16 : 32-4 . 45 . Potter WZ, Calil HM, Sutfin TA, et al. Active metabolites of imipramine and desipramine in man . Clin Pharmacol Ther 1982 ; 31 : 393-401 . 46 . Furlanut M, Montanari G, Benetello P, Bonin P, Schiaulini P, Pellegrino PA . Steadystate serum concentrations of imipramine, its main metabolites and clinical response in primary enuresis . Pharmacol Res 1989 ; 21 : 561-6 . 47 . Nordin C, Bertilsson L, Siwers BO . Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline . Clin Pharmacol Ther 1987 ;42 :10-19 . 48 . Steiner E, Dumont E, Spina E, Dahlqvist R. Inhibition of desipramine 2-hydroxylation by quinidine and quinine . Clin Pharmacol Ther 1988 ; 43 : 577-8 1 . 49 . Cooke RG, Warsh JJ, Stancer HC, Reed KL, Persad E . The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma . Clin Pharmacol Ther 1984 ; 36 : 343-8 . 50 . Bresen K, Gram LF, Klysner R, Bech P . Steady-state levels of imipramine and its metabolites : significance of dose-dependent kinetics . Eur J Clin Pharmacol 1986 ; 30 : 43-9 . 51 . Bjerre M, Gram LF, Kragh-Serensen P, et al. Dose-dependent kinetics of imipramine in elderly patients. Psychopharmacology 1981 ; 75 : 354-7 . 52 . Preskorn SH, Mac DS . Plasma levels of amitriptyline: effect of age and sex . J Clin Psychiat 1985 ; 46 : 276-7 . 53 . Gram IF. Imipramine : a model substance in pharmacokinetic research . Acta Psychiatr Scand 1988 ; 78 (Suppl 345) :81-4 . 54 . Biggs SR, Chasseaud LF, Hawkins DR, Midgley I . Determination of amitriptyline and its major basic metabolites in human urine by high-performance liquid chromatography. Drug Metab Dispos 1979 ; 7 : 233-6 . 55 . Potter WZ, Rudorfer MV, Lane EA . Active metabolites of antidepressants : pharmacodynamics and relevant pharmacokinetics . In : Usdin E, Asberg M, Bertilsson L, Sjögvist F, eds . Frontiers in biochemical and pharmacological research in depression . New York: Raven Press, 1984 : 373-90 .
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