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PubMed1986

Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers.

Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P less than 0.01) with all three parameters of amitriptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs = -0.89, -0.78, and -0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.

Administration, Oral↗
PubMed1992

Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes.

In 26 hospitalized patients with depression, a combined pharmacogenetic test with dextromethorphan, a substrate of cytochrome P450IID6, and mephenytoin, the S-form of which is hydroxylated by a P450IIC isozyme, was carried out before amitriptyline therapy. Metabolites were determined in 24-hour urine samples collected on treatment day 8, and the contributions of individual compounds, including the four isomers of 10-hydroxyamitriptyline and 10-hydroxynortriptyline to total excretion were calculated. Formation of (-)-E-10-hydroxyamitriptyline and (-)-E-10-hydroxynortriptyline apparently depends on the activity of cytochrome P450IID6 because negative correlations existed between the log metabolic ratio of dextromethorphan and the relative quantities of these enantiomers. In contrast, correlations were positive for nortriptyline, (+)-E-10-hydroxynortriptyline, (-)-Z-10-hydroxynortriptyline, and (+)-Z-10-hydroxynortriptyline. The mephenytoin hydroxylase seems to participate in side-chain demethylation to the secondary and primary amines, because the log metabolic ratio of mephenytoin correlated negatively with the relative quantity of E-10-hydroxydidesmethylamitriptyline and positively with that of amitriptyline and its N-glucuronide.

Adult↗
PubMed1996

Enzyme kinetic modelling as a tool to analyse the behaviour of cytochrome P450 catalysed reactions: application to amitriptyline N-demethylation.

1. To determine kinetic parameters (Vmax, K(m)) for cytochrome P450 (CYP) mediated metabolic pathways, nonlinear least squares regression is commonly used to fit a model equation (e.g., Michaelis Menten [MM]) to sets of data points (reaction velocity vs substrate concentration). This method can also be utilized to determine the parameters for more complex mechanisms involving allosteric or multi-enzyme systems. Akaike's Information Criterion (AIC), or an estimation of improvement of fit as successive parameters are introduced in the model (F-test), can be used to determine whether application of more complex models is helpful. To evaluate these approaches, we have examined the complex enzyme kinetics of amitriptyline (AMI) N-demethylation in vitro by human liver microsomes. 2. For a 15-point nortriptyline (NT) formation rate vs substrate (AMI) concentration curve, a two enzyme model, consisting of one enzyme with MM kinetics (Vmax = 1.2 nmol min-1 mg-1, K(m) = 24 microM) together with a sigmoidal component (described by an equation equivalent to the Hill equation for cooperative substrate binding; Vmax = 2.1 nmol min-1 mg-1, K' = 70 microM; Hill exponent n = 2.34), was favoured according to AIC and the F-test. 3. Data generated by incubating AMI under the same conditions but in the presence of 10 microM ketoconazole (KET), a CYP3A3/4 inhibitor, were consistent with a single enzyme model with substrate inhibition (Vmax = 0.74 nmol min-1 mg-1, K(m) = 186 microM, K1 = 0.0028 microM-1). 4. Sulphaphenazole (SPA), a CYP2C9 inhibitor, decreased the rate of NT formation in a concentration dependent manner, whereas a polyclonal rat liver CYP2C11 antibody, inhibitory for S-mephenytoin 4'-hydroxylation in humans, had no important effect on this reaction. 5. Incubation of AMI with 50 microM SPA resulted in a curve consistent with a two enzyme model, one with MM kinetics (Vmax = 0.72 nmol min-1 mg-1, K(m) = 54 microM) the other with 'Hill-kinetics' (Vmax = 2.1 nmol min-1 mg-1, K' = 195 microM; n = 2.38). 6. A fourth data-set was generated by incubating AMI with 10 microM KET and 50 microM SPA. The proposed model of best fit describes two activities, one obeying MM-kinetics (Vmax = 0.048 nmol min-1 mg-1, K(m) = 7 microM) and the other obeying MM kinetics but with substrate inhibition (Vmax = 0.8 nmol min-1 mg-1, K(m) = 443 microM, K1 = 0.0041 microM-1). 7. The combination of kinetic modelling tools and biological data has permitted the discrimination of at least three CYP enzymes involved in AMI N-demethylation. Two are identified as CYP3A3/4 and CYP2C9, although further work in several more livers is required to confirm the participation of the latter.

Amitriptyline↗
PubMed1997

Cytochromes P450 mediating the N-demethylation of amitriptyline.

AIMS: Using human liver microsomes and heterologously expressed human enzymes, we have investigated the involvement of CYPs 1A2, 2C9, 2C19, 2D6 and 3A4 in the N-demethylation of amitriptyline (AMI), with a view to defining likely influences on its clinical pharmacokinetics. METHODS: The kinetics of formation of nortriptyline (NT) from AMI were measured over the substrate concentration range 1-500 microM, using liver microsomes from four extensive metabolisers (EM) and one poor metaboliser (PM) with respect to CYP2D6 activity. RESULTS: The data were best described by a two-site model comprising a Michaelis-Menten function for a high affinity site and a Hill function for a low affinity site. The activity at the low affinity site was eliminated by triacetyloleandomycin and ketoconazole, selective inhibitors of CYP3A4, such that the kinetics were then described by a two-site model comprising two Michaelis-Menten functions. A further decrease in activity was associated with the addition of the CYP2C9 inhibitor sulphaphenazole such that the residual kinetics were best described by a single Michaelis-Menten function. The addition of quinidine, a selective inhibitor of CYP2D6, along with triacetyloleandomycin and sulphaphenazole produced an additional decrease in the rate of NT formation in all but the PM liver, but did not completely eliminate the reaction. The remaining activity was best described by a single Michaelis-Menten function. Inhibitors of CYP1A2 (furafylline) and CYP2C19 (mephenytoin) did not impair NT formation. Microsomes from yeast cells expressing CYP2D6 and from human lymphoblastoid cells expressing CYP3A4 or CYP2C9-Arg N-demethylated AMI, but those from cells expressing CYPs 1A2 and 2C19 did not. CONCLUSIONS: We conclude that CYPs 3A4, 2C9 and 2D6 together with an unidentified enzyme, but not CYPs 1A2 and 2C19, mediate the N-demethylation of AMI. Thus, the clinical pharmacokinetics of AMI would be expected to depend upon the net activities of all of these enzymes. However, the quantitative importance of each isoform is difficult to predict without knowledge of the exposure of the enzymes in vivo to AMI.

Amitriptyline↗
PubMed1997

Symptoms of major depression and tricyclic side effects in primary care patients.

OBJECTIVE: To examine the prevalence and course of symptoms resembling side effects of tricyclic antidepressants among primary care patients experiencing major depression and receiving nortriptyline pharmacotherapy. DESIGN: Prospective cohort study. PATIENTS: Seventy-five patients meeting DSM-III-R criteria for a current major depression. SETTING: Four Pittsburgh (Pa.) ambulatory health centers affiliated with residency programs. MEASUREMENTS AND MAIN RESULTS: Symptoms resembling tricyclic side effects were assessed at baseline and at monthly intervals using the Somatic Symptoms Checklist. The Hamilton Rating Scale for Depression and Diagnostic Interview Schedule were used to assess depressive severity and history of generalized anxiety or panic disorder, respectively. Symptoms resembling tricyclic side effects, including thirst (54%), palpitations (51%), and dry mouth (48%), were commonly experienced before commencing pharmacotherapy. Patients with severe depressive episodes and those with a history of an anxiety or panic disorder had significantly more physical symptoms than those with milder episodes of depression and were more likely to drop out of care (n = 25) before completing the acute phase of pharmacotherapy. Patients who completed the acute phase of pharmacotherapy and those who entered its continuation phase (n = 43) experienced significant reduction in many depressive and physical symptoms (p < .001). CONCLUSIONS: Symptoms resembling tricyclic side effects are common among depressed primary care patients before beginning pharmacotherapy and generally remit with the depressive episode. Better awareness of major depression's somatic effects and the consequences of therapy could result in better management of both physicians' and patients' expectations regarding antidepressant pharmacotherapy.

Adolescent↗
PubMed2002

Charcoal enhancement of treatment for tricyclic-induced mania.

Induction of mania by tricyclic antidepressants (TCAs) is controversial, with indirect evidence for and against it. Unusual direct evidence of it was observed in a 77-year-old female patient having ingested an amitriptyline overdose. Mania developed while the TCA blood levels were high, and responded to a combination of charcoal and valproate. However, mania reappeared when charcoal was discontinued, and disappeared again when it was restarted. This time course suggests a therapeutic advantage for adding charcoal to valproate in treating tricyclic-induced mania. Presumably, charcoal might have removed a mania-inducing metabolite of amitriptyline. Moreover, repeated doses of oral activated charcoal accelerated the elimination of TCA from the blood stream to several times its original rate, which is consistent with interruption of the enterohepatic circulation. This enhanced elimination and improved outcome illustrate the value of repeated charcoal doses after TCA overdose, and suggest its use when mania develops in a patient who takes an antidepressant, at least amitriptyline or nortriptyline.

Aged↗
PubMed2003

Predictors of therapeutic effects in amitriptyline treatment--1. Plasma drug levels.

OBJECTIVE: To analyze the spectrum of relationships between clinical effects of amitriptyline (At) treatment after 2 and 4 weeks (wks) and plasma levels of At, nortriptyline (Nt), At+Nt, demethylation rate of At, treatment modalities, age, and gender. METHODS: Patients with major depression (ICD 10: F31-F33) and a HAMD-21 total score of 15-41 received At on a dosage schedule chosen by the doctor for at least 4 wks. Plasma drug levels were assessed at baseline and at wks 2 and 4. RESULTS: Of the 58 patients enrolled in the study, 47 (15males, 32 females) were eligible for statistical analysis. An early response by wk 2 (decrease in HAMD-21 score of at least 50 % from baseline) was observed in 34.0 % of patients, and after 4 wks, the response rate was 63.8 % (males 86.6 %, females 53.1 %). There was a low, negative, and significant correlation between percent reduction in HAMD and steady state At concentration only at wk 2 (n = 47 r Sp. = -0.306 p < 0.05). However, the correlation was dependent on the degree of At demethylation and treatment modalities. A ratio of Nt/At >1 was observed in 23 patients; of these, 11 (47.8 %) were non-responders by wk 4. A low rate of demethylation (Nt/At </= 1) in 24 patients was associated with a lower frequency of non-response (6/24 = 25.0 %). In the latter subgroup, the 2-wk At plasma concentration varied between 20 and 240 ng/ml, and all patients with </= 110 ng At /ml were responders by wk 4. On the other hand, in the Nt/At >1 group, the non-responders were distributed in the whole range of observed At plasma concentrations (20-150 ng/ml). Only in patients with Nt/At </= 1 and constant doses from wk 1 to wk 4 (n = 14) was a strong, linear, and negative correlation between percent reduction in HAMD and plasma At, Nt, or At+Nt concentrations found for the 2-wk data (r Sp. = -0.754, -0.716, and -0.732, respectively), but not after 4 wks. CONCLUSIONS: The frequently assumed dependence of clinical effects on plasma drug levels is not a simple function. There most likely exist different patterns of relationships with partially unknown backgrounds. The ratio Nt/At may become a discriminating variable in future studies on the nature of plasma level-therapeutic effect relationship in At treatment of major depression.

Adult↗
PubMed1985

Single oral dose pharmacokinetics of amitriptylinoxide and amitriptyline in humans.

Eleven healthy volunteers were examined in a pharmacokinetic study. After oral administration of 50 mg amitriptylinoxide or 50 mg amitriptyline the plasma levels of amitriptylinoxide and its main metabolites amitriptyline and nortriptyline were investigated over 24 hours. The results indicate that amitriptylinoxide is more rapidly absorbed than amitriptyline and eliminated with a mean half-life of 1.5 hours. The change with time in the levels of amitriptyline formed from the oxide is similar to that of amitriptyline after ingestion of amitriptyline. However, the plasma concentration of amitriptylinoxide, reflected by the area under the time curve (AUC), exceeds that of its metabolite amitriptyline twelvefold.

Administration, Oral↗
PubMed2003

Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution.

A 29-year-old woman ingested 8 g of nortriptyline and presented to the emergency department with coma, hypotension, and widened QRS interval. After intubation, gastric lavage, hyperventilation, and therapy with intravenous normal saline solution, sodium bicarbonate boluses (rapid intravenous push), and high doses of norepinephrine and dopamine, she transiently improved, only to deteriorate on arrival to the ICU. Because her arterial pH was alkalemic at 7.5 at this point, she was given additional sodium in the form of 200 mL of 7.5% NaCl by means of rapid intravenous infusion (intravenous push) to treat hypotension and widening QRS interval with ventricular ectopy. A continuous 12-lead ECG documented narrowing of her QRS interval with concomitant improvement of hypotension within 3 minutes of hypertonic saline solution infusion. Hypertonic saline solution should be considered for wide complex QRS and hypotension caused by tricyclic antidepressant-induced cardiotoxicity that is unresponsive to standard therapies.

Adult↗
PubMed2000

Determination of residues in the norepinephrine transporter that are critical for tricyclic antidepressant affinity.

The norepinephrine (NET) and dopamine (DAT) transporters are highly homologous proteins, displaying many pharmacological similarities. Both transport dopamine with higher affinity than norepinephrine and are targets for the psychostimulants cocaine and amphetamine. However, they strikingly contrast in their affinities for tricyclic antidepressants (TCA). Previous studies, based on chimeric proteins between DAT and NET suggest that domains ranging from putative transmembrane domain (TMD) 5 to 8 are involved in the high affinity binding of TCA to NET. We substituted 24 amino acids within this region in the human NET with their counterparts in the human DAT, resulting in 22 different mutants. Mutations of residues located in extra- or intracytoplasmic loops have no effect on binding affinity of neither TCA nor cocaine. Three point mutations in TMD6 (F316C), -7 (V356S), and -8 (G400L) induced a loss of TCA binding affinity of 8-, 5-, and 4-fold, respectively, without affecting the affinity of cocaine. The triple mutation F316C/V356S/G400L produced a 40-fold shift in desipramine affinity. These three residues are strongly conserved in all TCA-sensitive transporters cloned in mammalian and nonmammalian species. A strong shift in TCA affinity (IC(50)) was also observed for double mutants F316C/D336T (35-fold) and S399P/G400L (80-fold for nortriptyline and 1000-fold for desipramine). Reverse mutations P401S/L402G in hDAT did not elicit any gain in TCA affinities, whereas C318F and S358V resulted in a 3- and 10-fold increase in affinity, respectively. Our results clearly indicate that two residues located in TMD6 and -7 of hNET may play an important role in TCA interaction and that a critical region in TMD8 is likely to be involved in the tertiary structure allowing the high affinity binding of TCA.

Amino Acid Sequence↗
PubMed2003

Mechanism-based inhibition of CYP activities in rat liver by fluoxetine and structurally similar alkylamines.

1. The inhibition of cytochrome P450 (CYP)-mediated substrate oxidations by alkylamine-based drugs was investigated in rat hepatic microsomes. The effects of pre-incubation of the drugs with NADPH-fortified microsomes on inhibition potency was evaluated in relation to the formation of metabolite intermediate (MI) complexes with CYP in vitro. 2. The selective serotonin-reuptake inhibitor fluoxetine (FLU) emerged as a potent and preferential inhibitor of CYP2C11 in rat liver microsomes. After FLU biotransformation in NADPH-supplemented microsomes, IC50 values of 2 and 1 microM were determined against CYP2C11-dependent testosterone 2alpha- and 16alpha-hydroxylation; in the absence of pre-incubation, the corresponding IC50 values were 47 and 39 microM. MI complexation of CYP appeared to contribute significantly to inhibition by FLU, as evidenced by the 21% decrease in apparent microsomal CYP content produced by 50 microM FLU in the presence of NADPH. 3. The secondary amines nisoxetine (NIS), and especially, desipramine (DES) and nortriptyline (NOR), also inhibited CYP2C11 and generated MI complexes with microsomal CYP. In contrast, with the exception of SKF-525-A, tertiary alkylamines (10 compounds) inhibited specific CYP activities but did not form MI complexes. Pre-incubation of these agents with NADPH-supplemented microsomes did not enhance inhibition of CYP activities, thus suggesting that formation of inhibitory metabolites was minimal for these compounds. 4. These findings implicate drug-mediated MI complexation of CYPs in the inhibition of hepatic biotransformation processes by secondary alkylamines. In contrast, tertiary amines did not generate significant quantities of CYP-MI complexes under the test conditions. Despite their diffusion from the CYP active site, inhibition produced by tertiary amines and stable metabolites of other drugs may be significant. However, such inhibition would be of shorter duration than that from MI complexation, which involves quasi-covalent binding to the haem and prevention of oxygen activation.

Adrenergic Uptake Inhibitors↗
PubMed1997

Metabolism of amitriptyline with CYP2D6 expressed in a human cell line.

1. Expressed human cytochrome P450 enzyme CPY2D6 was used to metabolize amitriptyline (AMI). It was established that CYP2D6 not only catalyzed ring 10-hydroxylation of AMI, but also mediated its N-demethylation to nortriptyline (NT), as well as the formation of 10-hydroxy-NT from NT. When the metabolism of AMI by CYP2D6 was repeated in the presence of quinidine, none of the metabolites, 10-hydroxy-AMI, NT and 10-hydroxy-NT, was formed. 2. Biochemical parameters of NT formation from AMI were determined, yielding Km = 47.48 +/- 1.32 microM; Vmax = 3.95 +/- 0.11 nmol/h/mg protein. The same parameters were calculated for the formation of 10-hydroxy-AMI (E + Z-isomers) from AMI, yielding Km = 10.70 +/- 0.20 microM; Vmax = 8.99 +/- 0.47 nmol/h/mg protein. 3. The formation of 10-hydroxy-NT from AMI proceeded primarily via NT and to a much lesser extent via 10-hydroxy-AMI. 4. Quantitative analyses of AMI and its metabolites were difficult to reproduce when the metabolites were analysed underivatized. Two derivatization procedures, acetylation and trifluoroacetylation, were employed to improve assay reproducibility.

Acylation↗
PubMed2006

Developments in pharmacotherapy for tobacco dependence: past, present and future.

In the mid-1970s there were no effective pharmacological treatments for tobacco dependence. The invention of nicotine gum was a major treatment advance and also greatly helped our understanding of the nature of tobacco dependence. There are now eight effective pharmacotherapies (nicotine gum, patch, nasal spray, inhaler, lozenge/tablet, bupropion, nortriptyline and clonidine) available to aid smoking cessation. Other non-nicotine agents that show promise are under investigation, including glucose, rimonabant, selegiline and varenicline. Greater knowledge of the mechanisms of action of the effective non-nicotine agents should lead to better understanding of the nature of tobacco dependence. Future research into optimal treatments should examine long-term combination pharmacotherapy combined with improved psychosocial support that is partly designed to enhance medication compliance. In addition, there is a need for studies designed to evaluate the efficacy of pharmacotherapies in populations such as youth, pregnant smokers and smokers with co-occurring mental health problems.

Adolescent↗
PubMed2004

Bipolar II disorder: personality and outcome in two clinical samples.

OBJECTIVE: To compare the personality traits and disorders of patients with bipolar II disorder and major depression and to examine the impact on treatment outcome of a bipolar II diagnosis. METHOD: Patients from two clinical trials, a depressive sample (n = 195, 10% bipolar II) and a bulimic sample (n = 135, 16% bipolar II), were assessed for personality traits using DSM-IV criteria. Patients were randomised to treatments (fluoxetine or nortriptyline for depressive sample; cognitive behaviour therapy for bulimic sample) and followed for 3 years (depressive sample) or 5 years (bulimic sample) to assess the impact on outcome of a bipolar II diagnosis. RESULTS: Bipolar II patients were assessed as having more borderline, histrionic and schizotypal personality traits than patients with major depression. A baseline bipolar II diagnosis did not impact negatively on treatment outcome, and less than 5% of bipolar II patients developed bipolar I disorder during follow up. CONCLUSIONS: The low rate of conversion of bipolar II to bipolar I disorder and the lack of adverse impact of the diagnosis on outcome, questions the need for antimanic or mood stabiliser medication in most bipolar II patients.

Adrenergic Uptake Inhibitors↗
PubMed1997

Cardiovascular effects of tricyclic antidepressants in childhood asthma: a case series and review.

Children with asthma frequently have significant anxiety and depression that interfere with treatment outcome. Although the use of antidepressants may be helpful, in the one published study of antidepressant use in pediatric asthma, significant side effects necessitated discontinuance; these side effects were increased motor activity, impulsive behavior, insomnia, postural hypotension, premature auricular contractions, diastolic hypertension, and generalized seizure. The objective of this retrospective chart review was to examine whether antidepressants could be tolerated and administered safely to children on asthma medications. Forty pediatric inpatients (mean age 13.3 years, range 7-19) with varying levels of asthma severity (5 mild, 11 moderate, 24 severe) and an average duration of asthma treatment of 10.0 years were administered antidepressants while also taking an average of 5 medications for asthma (range 2-7). Ten of the patients had an additional comorbid medical diagnosis. There were 17 children diagnosed with a primary affective disorder; 7 with a primary anxiety disorder; and 16 with both an affective and anxiety disorder. Thirty-six children ultimately were continued on an antidepressant: 13 on desipramine, 9 on nortriptyline, 6 on imipramine, 4 on fluoxetine, 3 on bupropion, and 1 on sertraline. Significant cardiovascular side effects (tachycardia, hypertension, and postural hypotension) occurred in 4 subjects on tricyclic antidepressants (TCAs) and 1 subject on a non-TCA (fluoxetine); 3 of these subjects were able to continue treatment with an antidepressant. Two subjects were taken off antidepressants because of hypomanic symptoms (increased motor activity, mood lability, impulsive behavior, and insomnia). No medications were discontinued because of electrocardiogram changes, arrhythmias, or seizures. Doses of TCAs were comparable to those in previous studies, but the asthma medications differed. Discussion of current anti-asthmatic medications and potential for interactions with antidepressants is included.

Adolescent↗
PubMedDate not supplied

Use of the EMITtox serum tricyclic antidepressant assay for the analysis of urine samples.

The EMITtox serum tricyclic antidepressant (TCA) assay is intended for use with serum or plasma. Currently, there are no commercially available immunoassay kits available for the detection of TCAs in urine. The proposed method utilizes the EMITtox serum TCA assay for the direct analysis of urine samples. The minimum detectable concentration of nortriptyline in urine is 25 ng/mL. The within-run CV was determined to be 0.6% and the between-run CV was 2.6%. The TCA assay cross-reacts with phenothiazines and antihistamines. The proposed methodology should be applicable to other EMIT serum assays to allow their use with urine.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Propylene glycol as a vehicle for percutaneous absorption of therapeutic agents.

Propylene glycol (PG) was evaluated as a vehicle for the in vivo percutaneous absorption of the hydrochloride salts of desipramine, nortriptyline, procainamide, and N-acetyl-procainamide. Each drug was administered topically to hairless (hr-1/hr-1) mice in water and in aqueous 10% and 50% PG. Mean drug concentrations in blood, brain, heart, liver, and lung were measured by high-pressure liquid chromatography after either two or three hours of topical absorption. The presence of PG generally enhanced the absorption of each drug, and the degree of enhancement appeared to be related to the percentage of PG in the dosing solution.

Acecainide↗
PubMed1996

Distribution of venlafaxine in three postmortem cases.

Venlafaxine (V) is a second-generation antidepressant approved for use in the United States in 1993. It is a derivative of phenethylamine and is structurally unrelated to first- and other second-generation antidepressants. Nevertheless, its mechanism of action is similar to other antidepressants; it inhibits the reuptake of presynaptic norepinephrine and serotonin. Its major routes of elimination involve O and N demethylation. O-Desmethylvenlafaxine (ODV) is biologically active. Therapeutic concentrations of V and ODV are approximately 0.2 and 0.4 mg/L, respectively. Three cases of drug intoxication involving V are presented. V and ODV were identified by gas chromatography-nitrogen-phosphorus detection after alkaline extraction of the biological specimen. On an HP-5 column, V and ODV elute after bupropion and fluoxetine, but prior to the first-generation antidepressants, sertraline, amoxapine, and trazodone. V and ODV were confirmed by full scan electron impact gas chromatography-mass spectrometry. The heart-blood V and ODV concentrations (mg/L) in the three cases were 6.6 and 31; 84 and 15; and 44 and 50, respectively. In Case 1, acetaminophen and diphenhydramine were found in the heart blood at 140 and 2.6 mg/L respectively. In Case 2, amitriptyline, nortriptyline, and chlordiazepoxide were found in the blood at 2.8, 0.5 and 3.3 mg/L, respectively. In each case, the manner of death was suicide.

Acetaminophen↗