Elucidation of Degradation Behavior of Tricyclic Antidepressant Amoxapine in Artificial Gastric Juice.

The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and nortriptyline) in artificial gastric juice was investigated to estimate their pharmacokinetics in the stomach. As a result, among the eight TCAs, only AMX was degraded in artificial gastric juice. The degradation was a pseudo first-order reaction; activation energy (Ea) was 88.70 kJ/mol and activation entropy (ΔS) was -80.73 J/K·mol. On the other hand, the recovery experiment revealed that the degradation product did not revert to AMX and accordingly, this reaction was considered to be irreversible. In the AMX degradation experiment, peaks considered to be degradation products A (I) and B (II) were detected at retention times of around 3 min and 30 min in LC/UV measurements, respectively. Structural analysis revealed that compound (I) was [2-(2-aminophenoxy)-5-chlorophenyl]-piperazin-1-yl-methanone, a new compound, and compound (II) was 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one. As for the degradation behavior, it was estimated that AMX was degraded into (II) via (I), i.e., (II) was the final product. The results are expected to be useful in clinical chemistry and forensic science, including the estimation of drugs to be used at the time of judicial dissection and suspected drug addiction.

Investigation of the disposition of loxapine, amoxapine and their hydroxylated metabolites in different brain regions, CSF and plasma of rat by LC-MS/MS.

Loxapine represents an interesting example of old "new" drug and is recently drawing attention for its novel inhalation formulation for the treatment of both psychiatric and non-psychiatric disorders. It is extensively metabolized to several active metabolites with diverging pharmacological properties. To further pursue the contribution of metabolites to the overall outcome after loxapine administration, quantification of both loxapine and its active metabolites is essential. The current study developed a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of loxapine and its five metabolites (amoxapine, 7-hydroxy-loxapine, 8-hydroxy-loxapine, 7-hydroxy-amoxapine and 8-hydroxy-amoxapine) in rat brain tissues, plasma and cerebrospinal fluid (CSF). By evaluating the effects of perchloric acid and methanol on analyte recovery, the extraction methods were optimized and only small amounts of sample (100 µl for plasma and less than 100mg for brain tissue) were required. The lower limits of quantification (LLOQs) in brain tissue were 3 ng/g for loxapine and amoxapine and 5 ng/g for the four hydroxylated metabolites of loxapine. The LLOQs were 1 ng/ml for loxapine and amoxapine and 2 ng/ml for the four hydroxylated metabolites in plasma, and 10 ng/ml for all analytes in CSF. The developed method was applied to a pharmacokinetic study on rats treated with a low-dose loxapine by oral administration. Four hours after loxapine dosing, high levels of 7-hydroxy-loxapine were found throughout the ten brain regions examined (68-124 ng/g), while only trace amount of loxapine was measured in brain (<5 ng/g) and plasma (<3 ng/ml). The method provides a useful tool for both preclinical and clinical investigations on the dispositions of loxapine and its metabolites, which would help to elucidate their roles in neurotherapeutics.

Efecto de amoxapina en preparaciones de órgano aislado de cobaya y de rata "in vitro" / Effect of amoxapine on severa preparations of isolated guinea-pig and rat organ "in vitro"

OBJETIVO. Estudiar las modificaciones inducidas por amoxapina en las respuestas del íleon aislado de cobaya a acetilcolina e histamina, conducto deferente de rata a noradrenalina y dopamina y útero aislado de rata a histamina. MATERIAL Y MÉTODOS. Se utilizó ileon aislado de cobaya incubado en solución de Tyrode, conducto deferente de rata incubado en solución de Krebs-Henseleit y útero aislado de rata incubado en solución de Jalón. Se realizaron curvas dosis-efecto a acetilcolina, histamina, noradrenalina y dopamina en ausencia y en presencia de amoxapina y se calcularon los valores de pA2 y pD'2. RESULTADOS. La amoxapina se comporta como antagonista de los neurotransmisores estudiados. CONCLUSIONES. La amoxapina se comporta como estabilizador inespecífico de membrana (AU)

OBJETIVE. Study the modifications produced by amoxapine in the responses of isolated guinea-pig to acetylcholine and histamine, rat vas deferens to noradrenaline and dopamine and rat uterus to histamine. MATERIAL AND METHODS. Guinea-pig incubated in Tyrode solution were used. Dose-effect curves to acetylcholine and histamine were made in absence and in the presence of amoxapine. Rat vas deferens incubated in Krebs-Henseleit solution were used. Dose-effect to noradrenaline and dopamine were made in the absence and in the presence of amoxapine. Uterus of rat incubated in Jalon solution were used. Dose-effect curves to histamine were made in the absence and in the presence of amoxapine. pA2 and pD'2 were calculated. RESULTS. Amoxapine behave as antagonist of acetylcholine, histamine and dopamine. CONCLUSIONS. Amoxapine acts as unspecific membrane stabilizer (AU)

A fatal case of amoxapine poisoning under the influence of chronic use of psychotropic drugs.

A 43-year-old woman was found dead in a car in the supine position. She had been suffering from depression for 2 years and hesitation wounds on the left forearm and wrist were observed. On microscopic examination, pulmonary congestion and edema were observed with heart failure cells in many alveoli, thereby suggesting not only acute but also chronic heart failure. Drug screening in the blood by gas chromatography-mass spectrometry (GC-MS) revealed the presence of amoxapine and levomepromazine, and their concentrations in tissues were determined by GC-MS with three-step solvent extraction followed by acetylation. The concentration of amoxapine in the blood and liver was 0.86-1.77 and 18.76microg/ml, respectively; the levels were much higher than the therapeutic level but did not reach the lethal level. The concentrations of levomepromazine in tissues were within the therapeutic level. Based on the pathological and toxicological findings, the cause of death was determined to be amoxapine poisoning on the basis of chronic heart failure due to the chronic use of psychotropic drugs.

Loxapine intoxication: case report and literature review.

Loxapine is a dibenzoxazepine tricyclic compound used to treat schizophrenia in the United States since 1976. Metabolism includes demethylation to its primary metabolite, amoxapine. There are few documented reports of the disposition of loxapine in deaths due to overdose. This report discusses the overdose suicide of a 69-year-old white female found dead in her home by her husband. A prescription for loxapine (50-mg capsules) was found near the body. An autopsy was performed and heart blood, bile, vitreous humor, and gastric contents were submitted for toxicological analysis. The blood specimen was subjected to comprehensive testing that included volatile analysis by headspace gas chromatography (GC); acidic/neutral and basic drug screening by GC; benzodiazepine screening by high-performance liquid chromatography; opiate screening by modified immunoassay; and acetaminophen, salicylate, and ethchlorvynol screening by colorimetry. Loxapine and amoxapine were detected in the basic drug screen. No other drugs were detected in the case specimens. The respective concentrations of loxapine and amoxapine in each specimen were as follows: heart blood, 9.5 and 0.6 mg/L; bile, 28.8 and 4.7 mg/L; gastric, 278 mg/L and negative; and vitreous, 1.5 mg/L and negative. A review of the literature showed that the heart blood concentration of loxapine measured in this case was the highest reported to date. Based on the autopsy findings, patient history, and toxicology results, the cause of death was determined to be acute intoxication of loxapine and the manner, suicide.

In rat brain amoxapine enhances dopamine metabolism: pharmacokinetic variations of the effect.

When rats were given i.p. amoxapine, the drug was biotransformed to 7-hydroxyamoxapine, but not to 8-hydroxyamoxapine. The maximal concentrations of amoxapine and 7-hydroxyamoxapine in the serum and brain were found 30 min after the single injection, and the concentration of the former in the brain was higher than that of the latter. During the chronic treatment the concentration of amoxapine in the brain was much higher than that of 7-hydroxyamoxapine. A single administration of amoxapine increased the brain levels of dihydroxyphenylacetic acid and homovanillic acid. Their highest levels were observed 6 h after the injection. Repeated administration reduced the increases; chronic treatment caused tolerance to the enhancing effects on dopamine (DA) metabolism. Tolerance was observed in both striatum and hippocampus, but not in frontal cortex and hypothalamus. Single or chronic injection did not appear to change the level of DA in the brain. Amoxapine itself could be chiefly responsible for the enhancement of DA metabolism. In addition, the level of 3-methoxy-4-hydroxyphenylethyleneglycol in brain decreased transiently right after the injection of amoxapine, but the norepinephrine level did not seem to change following single or chronic administration of amoxapine.

Antidepressants, metabolites, and apparent drug resistance.

Antidepressant drugs are extensively metabolized prior to elimination from the body. These metabolites usually have biological and chemical properties different from those of the parent drug. This article explores the pharmacodynamic consequences of such metabolism as possibly contributing to failure to respond to or tolerate a drug. Differential side effects, especially of tricyclic antidepressant metabolites, are considered. Next, shifts in effects of presumed serotonin uptake inhibitors are described. Problems involving active metabolites of more novel compounds such as bupropion, amoxapine and trazodone range from possible reversal of response to prohibitive side effects. Finally, principles are deduced for identifying those cases in which metabolic considerations are most likely to be relevant to observed drug resistance.