Plasma concentrations of nortriptyline and its 10‐hydroxy metabolite in depressed patients‐relationship to the debrisoquine hydroxylation metabolic ratio.

Nordin, Conny; Siwers, Bo; Benitez, J.; Bertilsson, Leif

doi:10.1111/j.1365-2125.1985.tb02723.x

Cited by 65 publications

(19 citation statements)

References 14 publications

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“…CYP2D6 pharmacogenetics figure prominently in this process due to the number of clinically useful compounds (tricyclic antidepressants, serotonin selective reuptake inhibitors, and cardiovascular agents) that are dependent upon this polymorphically expressed enzyme for their elimination from the body. In particular, relationships between CYP2D6 genotype and/or phenotype and drug clearance (and as a result, plasma concentrations achieved) have been established for several agents with relatively narrow therapeutic ranges such as nortriptyline (Nordin et al, 1985;Yue et al, 1999), desipramine (Spina et al, 1997), paroxetine (Sindrup et al, 1992;Yoon et al, 2000), and venlafaxine (Lessard et al, 1999), although CYP2D6 phenotype appears to predict toxicity better than it predicts clinical efficacy (Spina et al, 1997;Lessard et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 Activities toward Model CYP2D6 Substrates Dextromethorphan, Bufuralol, and Debrisoquine

Marcucci

Pearce²,

Crespi³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Over 50 allelic variants of cytochrome P450 2D6 (CYP2D6) encoding fully functional, reduced-activity, or nonfunctional proteins have been described. Compared with Caucasians, studies in black populations demonstrate a tendency toward slower CYP2D6 activity, attributed in part to the presence of a variant allele associated with reduced activity, the CYP2D6*17 allele. To investigate the kinetic characteristics of this variant protein, expression constructs coding for CYP2D6.1, CYP2D6.2, and CYP2D6.17 gene products were prepared and transfected into mammalian COS-7 and insect (Trichoplusia ni) cells for expression. Microsomal fractions containing the expressed proteins were used to determine the kinetic parameters K m , V max , and intrinsic clearance (Cl int ) for the model substrates dextromethorphan, bufuralol, and debrisoquine. Relative to the wild-type CYP2D6.1 protein expressed in COS-7 cells, CYP2D6.17 exhibited a 2-fold higher K m and a 50% reduction in V max using dextromethorphan as the substrate. In contrast, no appreciable change in bufuralol K m was observed with CYP2D6.17 whereas V max was decreased by 50%. When expressed in the baculovirus expression system, CYP2D6.17 exhibited a 6-fold increase in K m but no change in V max with dextromethorphan as the substrate, a 2-fold higher K m and 50% reduction in V max with bufuralol, and a 3-fold increase in K m and no change in V max with debrisoquine relative to CYP2D6.1. These data indicate that CYP2D6.17 exhibits reduced metabolic activity toward all three commonly used CYP2D6 substrates, although specific effects on substrate affinity and turnover demonstrate some substrate dependence.

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Section: Discussionmentioning

confidence: 99%

Characterization of Cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 Activities toward Model CYP2D6 Substrates Dextromethorphan, Bufuralol, and Debrisoquine

Marcucci

Pearce²,

Crespi³

et al. 2002

Drug Metab Dispos

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“…Clinical studies with nortriptyline (Nordin et al, 1985) and imipramine (Br0sen et al,in preparation) have shown that both compounds cause moderate inhibition of the oxidation of debrisoquine and sparteine. This weaker effect compared with that of quinidine is in good agreement with their lower in vitro potency as inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Sparteine oxidation is practically abolished in quinidine‐treated patients.

Brinn

Brøsen²,

Gram³

et al. 1986

Brit J Clinical Pharma

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In eight patients a sparteine-test was carried out immediately before and after 1 week of treatment with quinidine 600-800 mg dayf1. Before treatment one patient was classified as a poor metaboliser (metabolic ratio: : 20), and seven patients as extensive metabolisers. During quinidine treatment, the formation of sparteine metabolites (2-and 5-dehydrosparteine) was practically abolished. Patients initially classified as extensive metabolisers thus exhibited the phenotype of poor metabolisers during quinidine treatment.

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“…The metabolism of nortriptyline, when administered as such, is simpler and is mediated mainly (Ͼ80% in EMs) by CYP2D6 (Bertilsson et al, 1980;Nordin et al, 1985;Olesen and Linnet, 1997;Venkatakrishnan et al, 1999). After giving a 25-mg dose to Caucasians, the mean nortriptyline AUCs in genotypic PMs, IMs, and UMs were 3.3-, 2.8-, and 0.7-fold that observed in EMs, with reciprocal changes in 10-hydroxynortriptyline concentrations .…”

Section: A Amitriptyline (Tertiary)/nortriptyline (Secondary)mentioning

confidence: 98%