Where is amitriptyline metabolized

Six-hundred and seventy-eight patients were included in this study, based on availability of DNA and serum levels of parent drug and main metabolite. We investigated the relationship between CYP2C19 genotypes and metabolic parameters, including serum levels corrected for dose and metabolic ratio MR.

Part of the variation in response and adverse effects is attributed to interindividual differences in metabolic activity. Together, they represent one-third of all antidepressants prescribed in this institute.

PowerPoint slide. Information on daily dose was available for patients. Information on co-medication was not collected. The use and publication of data on medication, CYP2C19 , and CYP2D6 genotype and serum levels for research purposes has been approved by the psychiatric hospital's research board.

For this study, patients were not subjected to any procedures besides routine clinical practice. Patients are informed on the use of data for research purposes, and data are excluded from research on objection. Blood was collected in the anticoagulant EDTA.

PCR products were visualized by agarose gel electrophoresis. On the basis of a publication by Sim et al. All routinely performed assays were validated using references samples and were subject to regular external quality controls.

Therapeutic drug monitoring was routinely performed for all patients. This method was an adaptation of a method described by Aymard et al. This method was an adaptation of a method described by Rop et al. Variance coefficient values were 0. The assays were subjected to regular external quality controls. Acetonitrile cat. The internal standards protriptyline. HCl cat. P and desmethylclozapine cat. D were supplied by Sigma-Aldrich, and amitriptyline. Lu C was supplied by Lundbeck Copenhagen, Denmark.

Cases were grouped according to genotype. A subset of data showed a significant difference in variances, a lack in normality of residuals, and large differences in sample size.

Transformation to log values did not eliminate these difference in variances and residuals. Group averages were calculated using the averages for individual patients.

Genotype frequencies and group characteristics are shown in Table 1. A total of patients were included in the association study for AT. Information on daily dose was available for 86 patients. This association did not reach significance. The concentration of the active metabolite NT, rather then AT itself, has been associated with side effects of AT therapy. Group characteristics of the patients included in the association study for CIT are shown in Table 4.

Though this mean value is based on four subjects, it might indicate unsatisfactory response at lower doses, leading to increased doses in an attempt to obtain a more satisfactory response. Group characteristics of the patients included in the association study for CLOM are shown in Table 5. However, daily dose was relatively high for this subgroup. However, daily dose was relatively low for this subgroup. In the SGD system described by Steimer et al.

These individual differences in concentration were not significant, except one. Serum levels indicate large interindividual differences in CYP2C19 activity. Nevertheless, they do show a trend toward lower levels of parent drug.

Its influence is shown in this study by the significant associations between CYP2D6 genotype and parent drug levels or metabolite levels. On the basis of relative serum levels, dose recommendations can be provided for specific genotype groups. Impact of polymorphisms of cytochrome-P isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting.

Eur J Clin Pharmacol ; 60 : — PubMed Google Scholar. Semi-quantitative CYP2D6 gene doses in relation to metabolic ratios of psychotropics. Eur J Clin Pharmacol ; 64 : — Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem ; 50 : — Beta blockers, cimetidine, hormonal contraceptives, methylphenidate, propoxyphene, selective serotonin reuptake inhibitors: May inhibit amitriptyline metabolism, increasing plasma levels and toxicity.

Use together cautiously. Centrally acting antihypertensives such as clonidine, guanabenz, guanadrel, guanethidine, methyldopa, reserpine : May decrease hypotensive effects of these drugs.

Monitor blood pressure. CNS depressants including analgesics, anesthetics, barbiturates, narcotics, tranquilizers : Increases sedation. Disulfiram, ethchlorvynol: May cause delirium and tachycardia.

Haloperidol, phenothiazines: Decrease amitriptyline metabolism and efficacy. Metrizamide: Increases risk of seizures. Sympathomimetics, including epinephrine, phenylephrine, and ephedrine commonly found in nasal sprays : May increase blood pressure. Warfarin: May increase PT and cause bleeding.

Evening primrose oil: May cause additive or synergistic effect, resulting in lower seizure threshold and increased risk of seizures. Discourage use together. Alcohol use: Additive effects are likely. Discourage alcohol use. Heavy smoking: Induces amitriptyline metabolism and decreases therapeutic efficacy. Discourage smoking. Sun exposure: May cause photosensitivity reactions.

Advise patient to take precautions. Adverse reactions CNS: coma, seizures, hallucinations, delusions, disorientation, ataxia, tremor, peripheral neuropathy, anxiety, insomnia, restlessness, drowsiness, dizziness, weakness, fatigue, headache, extrapyramidal reactions.

EENT: blurred vision, tinnitus, mydriasis, increased intraocular pressure. GI: dry mouth, nausea, vomiting, anorexia, epigastric distress, diarrhea, constipation, paralytic ileus. The FDA-approved drug label for amitriptyline states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses.

The FDA recommendations also include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6 1. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose compared to normal metabolizers and using therapeutic drug monitoring to guide dose adjustments. Excerpt Amitriptyline is a tricyclic antidepressant used in the treatment of several psychiatric disorders, including major depression, obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, post-traumatic stress disorder, and bulimia.