151
Forekc Sti Zmkrnuttil, 56 (1992) 151- 156 Elsevier Scientific Pubhshers Ireland Ltd.
BUPROPION AND ALCOHOL FATAL INTOXICATION: CASE REPORT
VERA RAMCHARITAR, and YALE H. CAPLAN
BARRY S. LEVINE,
Office of the Chief Medical Examiw, (VW
BRUCE A. GOLDBERGER
State of Maryland,
111
Perm Street, Baltimore, MD 21201
(Received February 25th, 1992) (Revision received March 25th, 1992) (Accepted May 19th, 1992)
Summary A fatality due to the ingestion of bupropion and ethanol is presented. Bupropion and its metabolites were extracted from severai tissues and identified using gas chromatography with nitrogenphosphorus and mass spectrometry detection. The concentrations of bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites in heart blood were 4.2, 5.0, 0.6 and 4.6 mg/i, respectively. The heart blood ethanol concentration was 0.27 gldl. In addition, bupropion was distributed as follows: subclavian blood, 6.2 mg/i; bile, 1.4 mg/l; kidney, 2.4 mg/l; liver, 1.0 mg/kg; stomach contents, 16 mg and urine, 37 mg/l. Key words: Bupropion; Metabolism; Fatal intoxication;
Gas chromatographylmass
spectrometry
Introduction
Bupropion (Wellbutrin@, 2-tert-butylamino-3 ’-chloropropiophenone) is a relatively new antidepressant structurally unrelated to the first generation antidepressants such as amitriptyline and imipramine. The drug is not a monoamine oxidase inhibitor, nor is it believed to have major effects on the amine pump [ll. Therefore, adverse effects prominent with tricyclic antidepressants, such as anticholinergic effects, orthostatic hypotension and drowsiness are not of major concern with bupropion [2]. The drug has been evaluated on depressed patients with cardiovascular disease with positive results [3]. Bupropion has not been associated with weight gain, another undesirable effect of the tricyclics. The most severe adverse effect associated with bupropion is dose-related seizures [2]. Bupropion is rapidly absorbed following oral administration and distributes into tissues. The beta-elimination half-life (- 14 h) is somewhat shorter than the
Correspondace to: Yale H. Caplan, clo National Center for Forensic Science, 1901 Sulphur Spring Road, Baltimore, MD 21227, USA. 0379-0738/92/$05.00
0 1992 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland Ltd.
152
? C-YH -CH3 NHC(CW,
èl
6, H,C- k-CH,OH
Bupropion
kH, Hydroxybupropion
YH ~WCH,h
YH
CH- YH-CH,
CH-CH-CH,
NHWH,), Cl
Erythroamino Alcohol Mb.
Fig. 1. Chemical structure
Cl
Threoamino Alcohol Mb.
of bupropion and its metabolites.
classical antidepressants [4]. Bupropion is extensively metabolized in man, with less than 1% of the dose appearing unchanged in the urine. Three alkaline extractable metabolites are produced, hydroxybupropion (morpholinol metabolite) and erythroamino and threoamino alcohol metabolites. The chemical structures of bupropion and its metabolites are shown in Fig. 1. The threoamino metabolite is the major urinary metabolite; however, together these four compounds account for only 20% of the administered dose [5]. Side chain cleavage metabolites such as m-chlorobenzoic acid and m-chlorohippuric acid have been proposed [6]. Preliminary studies have established a relationship between trough steady state plasma bupropion concentrations and antidepressant response. The minimum effective concentration of bupropion is 25 ng/ml. The optimal therapeutic range is 50- 100 ng/ml. At bupropion concentrations exceeding 100 ng/ml, a decrease in clinical response was observed [7]. The following is a case presented to the Office of the Chief Medical Examiner, State of Maryland in which bupropion was believed to be involved in the death of an individual. Case report
A 38-year-old female with a history of severe depression was found unresponsive in the middle of a dead-end street. Several prescription containers (bupropion, fluoxetine, flurazepam, lorazepam, ibuprofen, albuterol inhaler) and a soft drink container with - 100 ml of an alcoholic beverage were recovered from the scene. NO evidente of foul play was reported and no suicide note was present. The body was transported to the Office of the Chief Medical Examiner of the State of Maryland for complete autopsy. Autopsy revealed pulmonary congestion and edema with no other unusual findings. Heart and subclavian blood,
153
urine, bile, liver, kidney and stomach contents were submitted to the toxicology laboratory for toxicological analysis.
Experimental Materials Bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites of bupropion were obtained from Burroughs Wellcome Company and 100 mg/l methanolic solutions as the free base were prepared. Mepivacaine was acquired from Winthrop Pharmaceuticals and a 100 mg/l solution in methanol served as the internal standard for analysis. Sulfuric acid, sodium hydroxide, ammonium hydroxide and isopropanol were J.T. Baker ACS grade. Methanol, methylene chloride and n-butyl chloride were Fisher Optimae grade.
Extraction To 5.0 ml standard, fluid or tissue homogenate (1 part tissue plus 4 parts water), 2.0 ml 0.1 N sodium hydroxide, 100 ~1 internal standard solution and 21 ml n-butyl chloride were added. After mechanica1 rotation and centrifugation, the n-butyl chloride layer was separated and extracted with 3.0 ml 1.0 N sulfuric acid. The acid layer was removed, alkalinized with 0.5 ml ammonium hydroxide and extracted with 5.0 ml methylene chloride. The methylene chloride was transferred to a conical centrifuge tube and 200 ~1 isopropanol were added. The tube was vortexed and the methylene chloride was evaporated to the isopropanol layer at 40°C under a stream of breathing air, which was then transferred to an autosampler vial and chromatographed. Quantitation was based on the area ratio of each compound to the internal standard in comparison to three fortified standards. Appropriate dilution of specimens with distilled water was performed in order to ensure quantitation within the limits of the standard curve.
Instrumentation Bupropion and metabolite analyses were performed using a Hewlett-Packard 5880A gas chromatograph equipped with a nitrogen-phosphorus detector (GCNPD) and a Hewlett-Packard 7673A automatie liquid sampler. The column used was a HP-5 cross-linked 5% phenyl methyl silicone fused silica capillary column (25 m x 0.32 mm i.d. x 0.17 Pm film thickness). Helium was the carrier gas flowing at 1 mllmin. The injector temperature was 250°C and the detector temperature was 310°C. The oven temperature began at 100°C for 1 min, increased at 30”Clmin to 2OO”C, then increased at 10”Clmin to 260°C and finally increased at 2O”Clmin to 3OO’C and held for 8 min. Splitless injection mode was utilized. Confirmation of bupropion and metabolites was performed using a HewlettPackard 5890 Series 11 gas chromatograph interfaced with a Hewlett-Packard 5971A mass selective detector (GC/MS). Gas chromatographic conditions similar to the GC-NPD parameters were used.
154 *~u&w
44 Bupropion
b*c
4b Hydroxybuproplon
80
80
EO-
60;
40-
100
40 7 116
20
20 75
0 Mfz .>
*wance
lb0
44
139 , 168 14l
224 m 260
!A
0 huz ->
Erythroamlno Alcohol Mb.
139 _L.
224 L
_lP.2@
lb
zda'"
hreoamino Alcohol Mb
8060 40:
100
100
20 2 77 1.
0 Mz'Z ->
50
I ." 100
141
,&
150
77 1.
210 226 I ', 200
lg 100
172
150
20s ”2I 2m
Fig. 2. Electron impact mass spectra of bupropion and its metabolites.
Results and Discussion A comprehensive test for alcohol and drugs was performed on the blood and urine specimens in this case. This included: (i) a volatile screen for methanol, ethanol, acetone and isopropanol by automated headspace gas chromatography; (ii) a basic drug screen by GC-NPD; (iii) an acid drug screen by GC-NPD; (iv) color tests for salicylate, acetaminophen and ethchlorvynol and (v) morphine by radioimmunoassay. The heart blood ethanol concentration was 0.27 g/dl. The ethanol concentrations in the subclavian blood, vitreous humor and urine were 0.35, 0.35 and 0.22 g/dl, respectively. NO other volatiles were detected in the blood. The drug
TABLE 1 ANALYTICAL DATA FROM THE PRESENTED Specimen
Blood, heart (mg/l) Blood, subclavian (mg/l) Bile (mg/l) Kidney (mg/kg) Liver (mgkg) Stomach contents (mg) Urine (mg/l)
Bup~opion
4.2 6.2 1.4 2.4 1.0 16 37
CASE
Hydroxybupropion
Erythroamino alcohol
5.0
0.6
5.8 5.0
1.0 1.0
14 13 9 27
3.5 6.3 0.7 14
Threoamino alcohol 4.6 5.1 5.1 21 35 3.4 54
155
test in urine indicated the presence of bupropion and its metabolites, fluoxetine and flurazepam which were al1identified by GC-NPD and confirmed by full scan electron impact GCIMS. The mass spectra of bupropion and its metabolites are shown in Fig. 2. The heart blood contained 0.7 mg/l of fluoxetine. The concentrations of bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites are shown in Table 1. NO other drugs were detected. This was the first case of bupropion intoxication encountered in this laboratory. A review of the literature provided little useful analytical information. Bupropion and its three metabolites are easily extracted using a conventional alkaline extraction procedure. The compounds elute early from a 5% phenyl methyl silicone capillary column using oven temperature programming. The retention times for bupropion and its metabolites are later than the amphetamines and sympathomimetic amines, but are earlier than those observed with the tricyclic and other antidepressants. The mass spectrum of bupropion has a base peak of rnlx 44, with mlz 100 as the other abundant ion. The parent ion, mix 239 is identifiable, but is less than 1% of the total abundance. The three metabolites have similar spectra. The identification of bupropion by mass spectrometry is difficult because of the low molecular weight ions appearing in these spectra. The identification depends greatly upon chromatographic retention times as wel1 as the presence of these metabolites in a unique pattern. This is similar to the tricyclic antidepressants; for instance, amitriptyline and doxepin have very similar mass spectra, but can be easily distinguished by retention time. There has been little information in the literature concerning fatalities from bupropion or the distribution of the drug in human postmortem specimens. The heart blood concentration of bupropion observed in this case is approximately 40 times higher than the reported upper limit of the therapeutic range, strongly suggestive of an overdose. The 0.27 gldl blood ethanol concentration undoubtedly contributed to the toxicity of bupropion. The vitreous humor and urine ethanol concentrations, when compared to the blood ethanol concentration suggest that the decedent was drinking shortly before death. The blood fluoxetine concentration of 0.7 mg/l is in the therapeutic range and in combination with bupropion and ethanol, may have contributed to the death in this case. The tissue distribution of bupropion seen in this case presents a pattern not observed with other antidepressants. The blood has a higher concentration of parent drug compared to the liver and kidney, while the liver and kidney have higher concentrations of the metabolites than the blood. The usual distribution of antidepressants such as amitriptyline and imipramine indicate higher concentrations of parent drug and metabolite in the liver and kidney than in the blood 131. The threoamino alcohol metabolite is reported to be the major urinary metabolite of bupropion. This was confirmed in this case. The reduction of bupropion is apparently stereospecific to a significant extent. A similar metabolic pattern of the threoamino and erythroamino alcohol metabolites in the liver and kidney was observed. A threoamino to erythroamino alcohol metabolite ratio of about 5 to 1 was noted in the specimens from this case. After reviewing the case history, autopsy and toxicology findings, the medical
156
examiner ruled the cause of death in this case to be ethanol and bupropion intoxication. The marmer of death was suicide. References 1 2 3
4 5
6 7 8
A. Gilman, L. Goodman, T. Ral1 and F. Murad, Th.ePhurnuxological Basis of Therapeutics, 7th Edn., MacMillan Publishing Co., New York, 1985. P.E. Hayes and C.A. Kristoff, Adverse reactions to five new antidepressants. Clin. Phmmaq, 5 (1986) 471-480. S.P. Roose, G.W. Dalack, A.H. Glassman, S. Woodring, B.T. Walsh and E.G.V. Giardina, Cardiovascular effectc of bupropion in depressed patients with heart disease. Am. J. Psychiutry, 148 (1991) 512 - 516. A.A. Lai and D.H. Schroeder, Clinical pharmacokinetics of bupropion: a review. J. Clin. Psychiutry, 44 (1983) 82-84. C.L. DeVane, S.C. Laizure, J.T. Stewart, B.E. Kolts, E.G. Ryerson, R.L. Miller and A.A. Lai, Disposition of bupropion in healthy vohmteers and subjects with alcohol liver disease. J. CZin. l., 10 (1990) 328-332. PSyChOphUrmacO D.H. Schroeder, Metabolism and kinetics of bupropion. J. Cl&. Pqchiatq, 44 (1983) 79-81. S.H. Preskom, Antidepressant response and plasma concentrations of bupropion. J. Clin. Psychiutry, 44 (1983) 137- 139. R.C. Bsselt and R.H. Cravey, Diqositim of Toxic Drugs and Chmkals in Man, Yearbook Medical Publishers, Chicago, 1989.
Forekc Sti Zmkrnuttil, 56 (1992) 151- 156 Elsevier Scientific Pubhshers Ireland Ltd.
BUPROPION AND ALCOHOL FATAL INTOXICATION: CASE REPORT
VERA RAMCHARITAR, and YALE H. CAPLAN
BARRY S. LEVINE,
Office of the Chief Medical Examiw, (VW
BRUCE A. GOLDBERGER
State of Maryland,
111
Perm Street, Baltimore, MD 21201
(Received February 25th, 1992) (Revision received March 25th, 1992) (Accepted May 19th, 1992)
Summary A fatality due to the ingestion of bupropion and ethanol is presented. Bupropion and its metabolites were extracted from severai tissues and identified using gas chromatography with nitrogenphosphorus and mass spectrometry detection. The concentrations of bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites in heart blood were 4.2, 5.0, 0.6 and 4.6 mg/i, respectively. The heart blood ethanol concentration was 0.27 gldl. In addition, bupropion was distributed as follows: subclavian blood, 6.2 mg/i; bile, 1.4 mg/l; kidney, 2.4 mg/l; liver, 1.0 mg/kg; stomach contents, 16 mg and urine, 37 mg/l. Key words: Bupropion; Metabolism; Fatal intoxication;
Gas chromatographylmass
spectrometry
Introduction
Bupropion (Wellbutrin@, 2-tert-butylamino-3 ’-chloropropiophenone) is a relatively new antidepressant structurally unrelated to the first generation antidepressants such as amitriptyline and imipramine. The drug is not a monoamine oxidase inhibitor, nor is it believed to have major effects on the amine pump [ll. Therefore, adverse effects prominent with tricyclic antidepressants, such as anticholinergic effects, orthostatic hypotension and drowsiness are not of major concern with bupropion [2]. The drug has been evaluated on depressed patients with cardiovascular disease with positive results [3]. Bupropion has not been associated with weight gain, another undesirable effect of the tricyclics. The most severe adverse effect associated with bupropion is dose-related seizures [2]. Bupropion is rapidly absorbed following oral administration and distributes into tissues. The beta-elimination half-life (- 14 h) is somewhat shorter than the
Correspondace to: Yale H. Caplan, clo National Center for Forensic Science, 1901 Sulphur Spring Road, Baltimore, MD 21227, USA. 0379-0738/92/$05.00
0 1992 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland Ltd.
152
? C-YH -CH3 NHC(CW,
èl
6, H,C- k-CH,OH
Bupropion
kH, Hydroxybupropion
YH ~WCH,h
YH
CH- YH-CH,
CH-CH-CH,
NHWH,), Cl
Erythroamino Alcohol Mb.
Fig. 1. Chemical structure
Cl
Threoamino Alcohol Mb.
of bupropion and its metabolites.
classical antidepressants [4]. Bupropion is extensively metabolized in man, with less than 1% of the dose appearing unchanged in the urine. Three alkaline extractable metabolites are produced, hydroxybupropion (morpholinol metabolite) and erythroamino and threoamino alcohol metabolites. The chemical structures of bupropion and its metabolites are shown in Fig. 1. The threoamino metabolite is the major urinary metabolite; however, together these four compounds account for only 20% of the administered dose [5]. Side chain cleavage metabolites such as m-chlorobenzoic acid and m-chlorohippuric acid have been proposed [6]. Preliminary studies have established a relationship between trough steady state plasma bupropion concentrations and antidepressant response. The minimum effective concentration of bupropion is 25 ng/ml. The optimal therapeutic range is 50- 100 ng/ml. At bupropion concentrations exceeding 100 ng/ml, a decrease in clinical response was observed [7]. The following is a case presented to the Office of the Chief Medical Examiner, State of Maryland in which bupropion was believed to be involved in the death of an individual. Case report
A 38-year-old female with a history of severe depression was found unresponsive in the middle of a dead-end street. Several prescription containers (bupropion, fluoxetine, flurazepam, lorazepam, ibuprofen, albuterol inhaler) and a soft drink container with - 100 ml of an alcoholic beverage were recovered from the scene. NO evidente of foul play was reported and no suicide note was present. The body was transported to the Office of the Chief Medical Examiner of the State of Maryland for complete autopsy. Autopsy revealed pulmonary congestion and edema with no other unusual findings. Heart and subclavian blood,
153
urine, bile, liver, kidney and stomach contents were submitted to the toxicology laboratory for toxicological analysis.
Experimental Materials Bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites of bupropion were obtained from Burroughs Wellcome Company and 100 mg/l methanolic solutions as the free base were prepared. Mepivacaine was acquired from Winthrop Pharmaceuticals and a 100 mg/l solution in methanol served as the internal standard for analysis. Sulfuric acid, sodium hydroxide, ammonium hydroxide and isopropanol were J.T. Baker ACS grade. Methanol, methylene chloride and n-butyl chloride were Fisher Optimae grade.
Extraction To 5.0 ml standard, fluid or tissue homogenate (1 part tissue plus 4 parts water), 2.0 ml 0.1 N sodium hydroxide, 100 ~1 internal standard solution and 21 ml n-butyl chloride were added. After mechanica1 rotation and centrifugation, the n-butyl chloride layer was separated and extracted with 3.0 ml 1.0 N sulfuric acid. The acid layer was removed, alkalinized with 0.5 ml ammonium hydroxide and extracted with 5.0 ml methylene chloride. The methylene chloride was transferred to a conical centrifuge tube and 200 ~1 isopropanol were added. The tube was vortexed and the methylene chloride was evaporated to the isopropanol layer at 40°C under a stream of breathing air, which was then transferred to an autosampler vial and chromatographed. Quantitation was based on the area ratio of each compound to the internal standard in comparison to three fortified standards. Appropriate dilution of specimens with distilled water was performed in order to ensure quantitation within the limits of the standard curve.
Instrumentation Bupropion and metabolite analyses were performed using a Hewlett-Packard 5880A gas chromatograph equipped with a nitrogen-phosphorus detector (GCNPD) and a Hewlett-Packard 7673A automatie liquid sampler. The column used was a HP-5 cross-linked 5% phenyl methyl silicone fused silica capillary column (25 m x 0.32 mm i.d. x 0.17 Pm film thickness). Helium was the carrier gas flowing at 1 mllmin. The injector temperature was 250°C and the detector temperature was 310°C. The oven temperature began at 100°C for 1 min, increased at 30”Clmin to 2OO”C, then increased at 10”Clmin to 260°C and finally increased at 2O”Clmin to 3OO’C and held for 8 min. Splitless injection mode was utilized. Confirmation of bupropion and metabolites was performed using a HewlettPackard 5890 Series 11 gas chromatograph interfaced with a Hewlett-Packard 5971A mass selective detector (GC/MS). Gas chromatographic conditions similar to the GC-NPD parameters were used.
154 *~u&w
44 Bupropion
b*c
4b Hydroxybuproplon
80
80
EO-
60;
40-
100
40 7 116
20
20 75
0 Mfz .>
*wance
lb0
44
139 , 168 14l
224 m 260
!A
0 huz ->
Erythroamlno Alcohol Mb.
139 _L.
224 L
_lP.2@
lb
zda'"
hreoamino Alcohol Mb
8060 40:
100
100
20 2 77 1.
0 Mz'Z ->
50
I ." 100
141
,&
150
77 1.
210 226 I ', 200
lg 100
172
150
20s ”2I 2m
Fig. 2. Electron impact mass spectra of bupropion and its metabolites.
Results and Discussion A comprehensive test for alcohol and drugs was performed on the blood and urine specimens in this case. This included: (i) a volatile screen for methanol, ethanol, acetone and isopropanol by automated headspace gas chromatography; (ii) a basic drug screen by GC-NPD; (iii) an acid drug screen by GC-NPD; (iv) color tests for salicylate, acetaminophen and ethchlorvynol and (v) morphine by radioimmunoassay. The heart blood ethanol concentration was 0.27 g/dl. The ethanol concentrations in the subclavian blood, vitreous humor and urine were 0.35, 0.35 and 0.22 g/dl, respectively. NO other volatiles were detected in the blood. The drug
TABLE 1 ANALYTICAL DATA FROM THE PRESENTED Specimen
Blood, heart (mg/l) Blood, subclavian (mg/l) Bile (mg/l) Kidney (mg/kg) Liver (mgkg) Stomach contents (mg) Urine (mg/l)
Bup~opion
4.2 6.2 1.4 2.4 1.0 16 37
CASE
Hydroxybupropion
Erythroamino alcohol
5.0
0.6
5.8 5.0
1.0 1.0
14 13 9 27
3.5 6.3 0.7 14
Threoamino alcohol 4.6 5.1 5.1 21 35 3.4 54
155
test in urine indicated the presence of bupropion and its metabolites, fluoxetine and flurazepam which were al1identified by GC-NPD and confirmed by full scan electron impact GCIMS. The mass spectra of bupropion and its metabolites are shown in Fig. 2. The heart blood contained 0.7 mg/l of fluoxetine. The concentrations of bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites are shown in Table 1. NO other drugs were detected. This was the first case of bupropion intoxication encountered in this laboratory. A review of the literature provided little useful analytical information. Bupropion and its three metabolites are easily extracted using a conventional alkaline extraction procedure. The compounds elute early from a 5% phenyl methyl silicone capillary column using oven temperature programming. The retention times for bupropion and its metabolites are later than the amphetamines and sympathomimetic amines, but are earlier than those observed with the tricyclic and other antidepressants. The mass spectrum of bupropion has a base peak of rnlx 44, with mlz 100 as the other abundant ion. The parent ion, mix 239 is identifiable, but is less than 1% of the total abundance. The three metabolites have similar spectra. The identification of bupropion by mass spectrometry is difficult because of the low molecular weight ions appearing in these spectra. The identification depends greatly upon chromatographic retention times as wel1 as the presence of these metabolites in a unique pattern. This is similar to the tricyclic antidepressants; for instance, amitriptyline and doxepin have very similar mass spectra, but can be easily distinguished by retention time. There has been little information in the literature concerning fatalities from bupropion or the distribution of the drug in human postmortem specimens. The heart blood concentration of bupropion observed in this case is approximately 40 times higher than the reported upper limit of the therapeutic range, strongly suggestive of an overdose. The 0.27 gldl blood ethanol concentration undoubtedly contributed to the toxicity of bupropion. The vitreous humor and urine ethanol concentrations, when compared to the blood ethanol concentration suggest that the decedent was drinking shortly before death. The blood fluoxetine concentration of 0.7 mg/l is in the therapeutic range and in combination with bupropion and ethanol, may have contributed to the death in this case. The tissue distribution of bupropion seen in this case presents a pattern not observed with other antidepressants. The blood has a higher concentration of parent drug compared to the liver and kidney, while the liver and kidney have higher concentrations of the metabolites than the blood. The usual distribution of antidepressants such as amitriptyline and imipramine indicate higher concentrations of parent drug and metabolite in the liver and kidney than in the blood 131. The threoamino alcohol metabolite is reported to be the major urinary metabolite of bupropion. This was confirmed in this case. The reduction of bupropion is apparently stereospecific to a significant extent. A similar metabolic pattern of the threoamino and erythroamino alcohol metabolites in the liver and kidney was observed. A threoamino to erythroamino alcohol metabolite ratio of about 5 to 1 was noted in the specimens from this case. After reviewing the case history, autopsy and toxicology findings, the medical
156
examiner ruled the cause of death in this case to be ethanol and bupropion intoxication. The marmer of death was suicide. References 1 2 3
4 5
6 7 8
A. Gilman, L. Goodman, T. Ral1 and F. Murad, Th.ePhurnuxological Basis of Therapeutics, 7th Edn., MacMillan Publishing Co., New York, 1985. P.E. Hayes and C.A. Kristoff, Adverse reactions to five new antidepressants. Clin. Phmmaq, 5 (1986) 471-480. S.P. Roose, G.W. Dalack, A.H. Glassman, S. Woodring, B.T. Walsh and E.G.V. Giardina, Cardiovascular effectc of bupropion in depressed patients with heart disease. Am. J. Psychiutry, 148 (1991) 512 - 516. A.A. Lai and D.H. Schroeder, Clinical pharmacokinetics of bupropion: a review. J. Clin. Psychiutry, 44 (1983) 82-84. C.L. DeVane, S.C. Laizure, J.T. Stewart, B.E. Kolts, E.G. Ryerson, R.L. Miller and A.A. Lai, Disposition of bupropion in healthy vohmteers and subjects with alcohol liver disease. J. CZin. l., 10 (1990) 328-332. PSyChOphUrmacO D.H. Schroeder, Metabolism and kinetics of bupropion. J. Cl&. Pqchiatq, 44 (1983) 79-81. S.H. Preskom, Antidepressant response and plasma concentrations of bupropion. J. Clin. Psychiutry, 44 (1983) 137- 139. R.C. Bsselt and R.H. Cravey, Diqositim of Toxic Drugs and Chmkals in Man, Yearbook Medical Publishers, Chicago, 1989.
