Maprotiline metabolism appears to co‐segregate with the genetically‐ determined CYP2D6 polymorphic hydroxylation of debrisoquine.

Firkusny, Lucie; Ch, Gleiter

doi:10.1111/j.1365-2125.1994.tb04293.x

Cited by 39 publications

(11 citation statements)

References 12 publications

(9 reference statements)

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“…Our finding does not explain the case of rapid maprotiline metabolism reported (Vormfelde et al 1997) but characterisation of the enzyme status in this patient with respect to CYP2D6 and CYP1A2 was limited and does not exclude individual peculiarities of these enzymes with certainty. In contrast, our data are in agreement with a major but not exclusive role of CYP2D6 in overall maprotiline elimination (Baumann 1986; Firkusny & Gleiter 1994). Systematic in vivo studies should be conducted to substantiate this assumption.…”

Section: Discussionsupporting

confidence: 88%

“…Baumann (1986) assumed that at least one oxidative pathway of maprotiline co‐segregates with the genetic polymorphism of debrisoquine. Additionally, in a study investigating maprotiline effects on bronchoconstriction, the maximum concentration of maprotiline was 2.7 times greater and the AUC was 3.5 times higher in poor metabolisers (n=6) of debrisoquine than in extensive metabolisers (n=6) (Firkusny & Gleiter 1994). However, compared with other antidepressants maprotiline was reported to be better tolerated, suggesting that a genetic polymorphism may be less important for maprotiline pharmacokinetics (Alkalay et al 1980; Logue et al 1979).…”

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confidence: 99%

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Cytochrome P‐450 Enzymes Contributing to Demethylation of Maprotiline in Man

Brachtendorf¹,

Jetter²,

Beckurts³

et al. 2002

Pharmacology & Toxicology

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From case reports of patients treated with the tetracyclic antidepressant drug maprotiline, it appears that this drug is subject to polymorphic metabolism. Thus, we studied formation of the major maprotiline metabolite desmethylmaprotiline to identify the human cytochrome P-450 enzymes (CYP) involved. In incubations with human liver microsomes from two different donors, the substrate maprotiline was used at five different concentrations (5 to 500 mM). For selective inhibition of CYPs, quinidine (0.5-50 mM; CYP2D6), furafylline (0.3-30 mM; CYP1A2), ketoconazole (0.2-20 mM; CYP3A4), mephenytoin (20-200 mM; CYP2C19), chlorzoxazone (1-100 mM; CYP2E1), sulphaphenazole (0.2-100 mM; CYP2C9) and coumarin (0.2-100 mM; CYP2A6) were used. Desmethylmaprotiline concentrations were measured by HPLC, and enzyme kinetic parameters were estimated using extended Michaelis-Menten equations with non-linear regression. Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only. Formation rates of desmethylmaprotiline were consistent with a two enzyme model with a high (K M Ω71 and 84 mM) and a low (K M Ω531 and 426 mM) affinity site for maprotiline in the two samples, respectively. The high affinity site was competitively inhibited by quinidine (K i , c 0.13 and 0.61 mM), the low-affinity site was non-competitively inhibited by furafylline (K i , nc 0.11 and 1.3 mM). Thus it appears that CYP2D6 and CYP1A2 contribute to maprotiline demethylation. Based on the parameters obtained, for plasma concentrations of 1 mM 83% (mean) of desmethylmaprotiline formation in vivo is expected to be mediated by CYP2D6 while 17% only may be attributed to CYP1A2 activity.Maprotiline hydrochloride, 1-(3-methylaminopropyl)-dibenzo[b,e]bicyclo[2,2,2]octadiene hydrochloride, is a tetracyclic antidepressant (molecular weight 313.9 g/l, corresponding to 278.4 g/l for maprotiline base). It is a highly selective norepinephrine reuptake inhibitor (Baumann & Maître 1979), which is usually administered in daily oral doses of 75 to 150 mg. Maprotiline is almost completely bioavailable upon oral administration and metabolised extensively, as only 2 % of a dose are excreted unchanged in urine (Alkalay et al. 1980). The average biological half-life of unchanged maprotiline in plasma is 2 days, and binding to serum proteins reaches 88% for a wide concentration range. Therapeutic plasma concentrations of maprotiline are in the range of 200 to 300 ng/ml. A main primary metabolic step of maprotiline is the formation of desmethylmaprotiline ( fig. 1). Formation of hydroxylated metabolites including 3-OH-maprotiline and, less important, 2-OH-maprotiline appear to account for most of the remaining fraction. Secondary metabolic steps generate a number of other metabolites (Riess et al. 1975;Breyer-Pfaff et al. 1985).Many antidepressants are metabolised by the genetically polymorphic cytochrome P-450 enzyme CYP2D6, exposing

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Cytochrome P‐450 Enzymes Contributing to Demethylation of Maprotiline in Man

Brachtendorf¹,

Jetter²,

Beckurts³

et al. 2002

Pharmacology & Toxicology

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“…The AUC of maprotiline (metabolites not measured) was 3.5-fold higher in PMs than in EMs after 50 mg twice daily for 8 days, and the half-life was proportionately longer. Prolonged histamine-induced bronchoconstriction has been seen in PMs (Firkusny and Gleiter, 1994).…”

Section: Doxepin (Tertiary)/desmethyldoxepin (Secondary)mentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…19 There are contradictory data regarding the effects of CYP2D6 polymorphisms on metabolism of the tetracyclic antidepressant maprotiline: while in a patient group receiving monotherapy with 150 mg maprotiline, no differences in steady-state concentrations were detected due to the debrisoquine metabolizer status, 77 a study with healthy volunteers receiving 100 mg maprotiline over 7 days, revealed differences similar to those detected in tricyclics. 78 For mianserin, CYP2D6 mediates enantioselective hydroxylation of the more active S-( þ ) mianserin. For dose adjustments, the sum of S-( þ )-mianserin and the active desmethylmianserin was taken ( Table 2).…”

Section: Impact Of Cyp2d6 Polymorphisms On Dosing Of Antidepressantsmentioning

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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Maprotiline metabolism appears to co‐segregate with the genetically‐ determined CYP2D6 polymorphic hydroxylation of debrisoquine.

Cited by 39 publications

References 12 publications

Cytochrome P‐450 Enzymes Contributing to Demethylation of Maprotiline in Man

Cytochrome P‐450 Enzymes Contributing to Demethylation of Maprotiline in Man

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

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

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