Isolation and identification of hydroxylated maprotiline metabolites

Breyer-Pfaff, U.; Kroeker, M.; Winkler, Tammo; Kriemler, P.

doi:10.3109/00498258509045335

Cited by 13 publications

(10 citation statements)

References 14 publications

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“…To our knowledge, this is the first report demonstrating that maprotiline biotransformation co-segregates with that of debrisoquine. The major metabolites in urine are 3-hydroxymaprotiline and 3-hydroxydesmethylmaprotiline [14]. Our findings are in contrast to those of an earlier study [15] which concluded that PM of debrisoquine do not have higher plasma maprotiline concentrations than EM.…”

Section: Discussioncontrasting

confidence: 99%

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

Firkusny¹,

Ch²

1994

Brit J Clinical Pharma

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The plasma concentrations of the tetracyclic antidepressant maprotiline and its effect on histamine‐induced bronchoconstriction were measured after single (50 mg) and multiple (50 mg twice daily) oral doses in healthy subjects. Histamine‐induced bronchoconstriction was abolished after a single dose of maprotiline and this effect persisted throughout multiple dose treatment. The mean Cmax of maprotiline in six poor metabolisers (PM) of debrisoquine was 2.7‐fold greater than that in six extensive metabolisers (EM) and the mean AUC(0,48 h) was 3.5 times higher. The duration of the pulmonary effect of maprotiline after cessation of multiple dose treatment in EM was less than 3 weeks compared with at least 4 weeks in PM.

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Section: Discussioncontrasting

confidence: 99%

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

Firkusny¹,

Ch²

1994

Brit J Clinical Pharma

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“…Maprotiline is metabolized to desmethylmaprotiline (active) mainly (ϳ80% in EMs) by CYP2D6 (Brachtendorf et al, 2003). Other metabolites (e.g., hydroxy derivatives) (Breyer-Pfaff et al, 1985) may also be active. 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.…”

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

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…1. Maprotiline and its major metabolites (Riess et al 1975;Breyer-Pfaff et al 1985, the maprotiline metabolic ratio in this patient was still higher than expected for poor metabolisers of CYP2D6. There was no duplication of the CYP2D6*2A allele seen in genotyping, and ultra-rapid metabolism via a highly active CYP1A2 was precluded in this patient as well.…”

mentioning

confidence: 61%

“…In summary, the inhibition data set suggests that CYP2D6 is the high affinity and CYP1A2 is the low affinity binding site, respectively, for maprotiline N‐demethylation. For a substrate concentration of 1 μM (278 ng/ml), which corresponds to typical maprotiline plasma concentrations (Riess et al 1975; Breyer‐Pfaff et al 1985), CYP2D6 would be responsible for 83% and CYP1A2 for 17% of overall maprotiline N‐demethylation.…”

Section: Discussionmentioning

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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Isolation and identification of hydroxylated maprotiline metabolites

Cited by 13 publications

References 14 publications

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

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

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

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

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