Amitriptyline Pharmacokinetics and Clinical Response: II. Metabolic Polymorphism Assessed by Hydroxylation of Debrisoquine and Mephenytoin

Baumann, Pierre; Jonzier-Perey, Michèle; Koeb, L.; Küpfer, A; Tinguely, D; Schöpf, Josef

doi:10.1097/00004850-198604000-00002

Cited by 61 publications

(22 citation statements)

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“…and that their fluoxetine interaction level can be different. This hypothesis might be confirmed by using dextromethorphan and mephenytoin phenotyping in treated patients, before and after the drug association, dextromethorphan being a marker for hydroxylation pathway study and mephenytoin for déméthylation path way [20].…”

Section: Discussionmentioning

confidence: 87%

Tricyclic Antidepressant Plasma Levels after Fluoxetine Addition

Vandel¹,

Bertschy²,

Bonin³

et al. 1992

Neuropsychobiology

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After a review of a pharmacokinetic interaction between tricyclic antidepres-sants (TCA) and fluoxetine the authors report their own data. They confirm the existence of an interaction of TCA with fluoxetine, in clinical practice, but the fluoxetine was not associated in all cases with a marked increase of TCA plasma levels. The increase appeared especially high with clomipramine (n = 4) and imipramine (n = 3), and lower or dose-dependent with amitriptyline (n= 4). The pharmacokinetic change did not induce side effects in the patients, even when the total TCA plasma level increased to 965 (clomipramine) or 785 (imipramine) ng/ml. The authors then discuss the clinical implication and the possible mechanism of action.

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Section: Discussionmentioning

confidence: 87%

Tricyclic Antidepressant Plasma Levels after Fluoxetine Addition

Vandel¹,

Bertschy²,

Bonin³

et al. 1992

Neuropsychobiology

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“…Tricyclic antidepressants The group of tricyclic antidepressants undergoes similar biotransformation actions in the liver with CYP2D6 catalyzing hydroxylation reactions, [49][50][51]68,121,122 whereas demethylation of the parent drug is mediated by CYP2C19. Both metabolites are pharmacologically active and the demethylated metabolites are partially tricyclic drugs by themselves such as nortriptyline and desipramine, which are desmethylmetabolites of amitriptyline and imipramine, respectively.…”

Section: Impact Of Cyp2d6 Polymorphisms On Dosing Of Antidepressantsmentioning

confidence: 99%

“…Few studies provide quantitative data on adverse drug reactions. 49 induced seizures was reported in relation to CYP2D6 activity 145 and several studies showed a relationship between extrapyramidal side effects of antipsychotic drugs and CYP2D6 polymorphisms. 96,[146][147][148][149][150][151][152][153][154][155][156] However, compared to the large efforts made to evaluate pharmacokinetic differences due to CYP polymorphisms, few prospective studies on benefit of phenotyping or genotyping for therapeutic outcome have been conducted so far.…”

Section: Impact Of Cyp2c9mentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…6 CYP2D6 is characterized by a high interindividual variability in catalytic activity mainly caused by genetic polymorphisms. 7 The respective phenotype determined by CYP2D6 genotype is predicted by the number of functional CYP2D6 alleles, so that the presence of two, one or no functional CYP2D6-gene copies results in phenotype of, respectively, rapid or extensive metabolizer 9,10 (The situation is even more complex with the existence of functional but low-activity alleles such as CYP2D6*10 and influences other than genotype on CYP2D6 activity, but as data on therapeutic consequences of these factors is very limited, this is not considered here.…”

Section: Tricyclic Antidepressantsmentioning

confidence: 99%