Dextromethorphan and Mephenytoin Phenotyping of Patients Treated with Thioridazine or Amitriptyline

Baumann, Pierre; Meyer, Johann W.; Amey, M.; Baettig, Dominique; Bryois, Christian; Jonzier-Perey, Michèle; Koeb, L.; Monney, Christian; Woggon, B

doi:10.1097/00007691-199202000-00001

Cited by 64 publications

(39 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All but one patient (with a metabolic ratio of dextromethorphan = 1.980) were extensive metabolizers of dextromethorphan and mephenytoin. This poor metabolizer of dextromethorphan [he was not comedicated with thioridazine, which could interfere with the pharmacogenetic test (Baumann et al 1992)] was a responder to the combined CIT-FLUV treatment, but he required administration of metoclopramide after he experienced nausea. His plasma levels of CIT and DCIT were within the range of those observed in the other patients.…”

Section: Resultsmentioning

confidence: 99%

“…Other somatic medications were admitted if they did not interfere with the P-450 isozymes, especially CYP2D6, CYP2C19, CYP1A2 and CYP3A3 /4. At baseline, a combined dextromethorphan-mephenytoin pharmacogenetic test was carried out (Baumann et al 1992) for phenotyping patients with regard to CYP2D6 and CYP2C19, respectively. A metabolic ratio > 0.3 and an S / R ratio > 0.8 in the dextromethorphan and mephenytoin tests, respectively, were used to differentiate poor from extensive metabolizers.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

et al. 1996

View full text Add to dashboard Cite

The effect of comedication with fluvoxamine on the plasma concentrations of the enantiomers of citalopram and its metabolites in dextromethorphan/mephenytoin phenotyped patients pretreated with citalopram (CIT) was studied: seven female patients (45.1 +/- 13.9 years) suffering from a major depressive episode [ICD-10: F32.2 (n = 3 patients), F33.2 (n = 2), F32.10 (n = 1) or F32.11 (n = 1)], who were non-responders to a 3-week treatment with 40 mg/day CIT (From day-21 to day 0) (day 0: MADRS score > or = 12), were co-medicated for another 3 weeks with fluvoxamine (50 mg/day from day 1-7, 100 mg/day from day 14-21). All patients were extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6), except one patient, who had a genetic deficiency of CYP2D6. There was a significant increase of the plasma concentrations of S- and R-citalopram from day 0 (27 +/- 14 micrograms/l and 55 +/- 23 micrograms/l, respectively) to day 21 (83 +/- 38 micrograms/l and 98 +/- 44 micrograms/l, respectively), after addition of fluvoxamine (P < 0.02, for each comparison), and the mean ratio S/R-citalopram increased from 0.48 to 0.84. S-Citalopram inhibits more potently 5-HT uptake than R-citalopram: therefore, fluvoxamine increases the pharmacologically more active S-citalopram with some stereoselectivity. According to a previous in vitro study, this pharmacokinetic interaction occurs on the level of CYP2C19, but also of CYP2D6 and CYP3A4 which, in contrast to CYP1A2, contribute to the N-demethylation of citalopram and which are stereoselectively inhibited by fluvoxamine. All but one patient showed clinical improvement by a decrease of the MADRS score by at least 50% and a final score < or = 13 (mean +/- SD: day 0:30.6 +/- 9.2; day 21:11.0 +/- 6.5). Some patients showed minor symptoms, such as nausea and tremor, but the combined treatment was generally well tolerated.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

et al. 1996

View full text Add to dashboard Cite

show abstract

“…For CYP2D6 and CYP2C19, inhibitors are most relevant to consider. Bupropion, fluoxetine, quinidine, paroxetine, terbinafine and thioridazine have all demonstrated the ability to convert extensive metabolizers of dextromethorphan into a poor metabolizing phenotype by CYP2D6 inhibition [1,5,6,15,59]. Regarding CYP2C19, fluvoxamine and fluoxetine have been shown to perform a dose-dependent inhibition of the probe drug mephenytoin [17].…”

Section: Variability In Plasma Metabolite/drug Ratiosmentioning

confidence: 99%

The Complexity of Active Metabolites in Therapeutic Drug Monitoring of Psychotropic Drugs

et al. 2006

View full text Add to dashboard Cite

In therapeutic drug monitoring (TDM) practice of psychotropic agents, it is common to summarize plasma concentrations of parent drugs and metabolites when these are considered equipotent. However, there is no clear definition of the term equipotent and one should be aware that metabolites referred to as equipotent in the literature could display several-fold differences in affinities toward target proteins. The fact that the parent drug and metabolite may have different abilities to penetrate the blood-brain-barrier further complicates the picture. Potential differences in brain distribution imply that various metabolite/drug ratios representing the same total concentration in plasma reflect different active concentrations in the brain. Plasma metabolite/drug ratios could differ extensively according to metabolic phenotype and administration route. An example is risperidone where the plasma metabolite/drug ratio is 30-fold lower in cytochrome P450 2D6 poor metabolizers compared to ultrarapid metabolizers, and four-fold lower after intramuscular compared to oral administration. As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain. However, the relative drug-metabolite brain distribution needs to be quantified in humans to clarify to what degree drug and metabolite plasma levels reflect active brain concentrations. The present review illustrates the complexity of active metabolites in TDM with focus on amitriptyline, clomipramine, doxepin, imipramine, fluoxetine, venlafaxine and risperidone, all psychotropic drugs where target plasma concentration ranges are based on the sum of parent drug and metabolite. In addition, perspectives on the possibility of using distribution- and activity-weighted plasma concentrations are provided.

show abstract

“…The underlying drug interaction mechanism is considered to be SSRI inhibiton of CYP2D6 (17,18), one of the most important enzymes in the metabolism of TCAs (19,20). As a consequence, plasma levels of TCAs were increased, and serious adverse effects such as tremor, dysarthria, and cardiovascular toxicity were observed (11,14,15,21,22).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Efficacy of Fluvoxamine and Amitriptyline in Depression

et al. 2009

View full text Add to dashboard Cite

Abstract. Although often necessary for obtaining remission following major depressive disorder, combined antidepressant treatment is frequently associated with drug interactions and enhanced adverse drug effects. We investigated pharmacokinetic interactions following combined fluvoxamine and amitriptyline treatment and their impact on therapeutic efficacy and tolerability. Twenty-two inpatients with major depression [Hamilton Depression Scale (HAM-D) rating ≥18] were treated with either amitriptyline (75 mg/day), fluvoxamine (100 mg/day) or both. Blood samples, for determination of amitriptyline, its major metabolite nortritpyline, and fluvoxamine, were obtained after single dose administration and in steady-state. Therapeutic efficacy was evaluated using HAM-D and adverse drug effects were evaluated using the clinical global impression scale. Following combined treatment, steady-state plasma levels of nortriptyline were significantly decreased compared to monotherapy. HAM-D scores after two-week treatment showed that there was a better response to combined treatment. There was no significant difference in severity of adverse effects among groups. We observed a pharmacokinetic interaction between fluvoxamine and amitritpyline resulting in impaired metabolism of the later. However, no signifcant impact of the interaction on treatment safety was observed. Moreover, concomitant use of amitriptyline at 75 mg/day and fluvoxamine at 100 mg/day was well tolerated with a more prompt and stronger onset of clinical response compared to monotherapy in patients with major depression.

show abstract

Dextromethorphan and Mephenytoin Phenotyping of Patients Treated with Thioridazine or Amitriptyline

Cited by 64 publications

References 0 publications

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

The Complexity of Active Metabolites in Therapeutic Drug Monitoring of Psychotropic Drugs

Pharmacokinetics and Efficacy of Fluvoxamine and Amitriptyline in Depression

Contact Info

Product

Resources

About