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

Abstract

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

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…a. Maprotiline. 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.…”

Effects of the CYP2D6*10 alleles and co‐medication with CYP2D6‐dependent drugs on risperidone metabolism in patients with schizophrenia

“…All the patients had received risperidone for more than 1 week before the study. Fifty-eight patients (65.2%) also received co-medications that are reported to be CYP2D6-dependent: levomepromazine (Suzuki et al, 1997), chlorpromazine (Suzuki et al, 2001), bromperidol (Suzuki et al, 1997), haloperidol (Suzuki et al, 2001), olanzapine (Gossen et al, 2002), paroxetine (Spina et al, 2001), fluvoxamine (D'Arrigo et al, 2005), amitriptyline (Castberg et al, 2005), maprotiline (Brachtendorf et al, 2002), terbinafine (Castberg et al, 2005, cimetidine (Madeira et al, 2004), mexiletine (Hara et al, 2005). The patients' compliance was confirmed by the nursing staff.…”

The Inhibitory Effect of Amoxapine on Cytochrome P450 Enzyme Activity in Human Liver Microsomes

“…It has been reported that TCAs are metabolized by several CYP isozymes [13][14][15][16][17][18][19] Since TCAs inhibit CYP2D6-mediated enzyme activity26,27), it is not surprising that numerous interactions between TCAs and commonly used drugs, which are categorized as substrates of CYP2D6, has been observed. However, the exact inhibitory potency of TCAs on CYP2D6 has not been extensively studied.…”

“…Competitive inhibition was observed with CYP2D6 and 3A4, while only a marginal effect was observed with CYP1A2, 2C9 and 2C19. In general, TCAs are mainly metabolized to N-demethylated and hydroxylated forms [13][14][15][16][17][18][19] . The hydroxylation reaction is mainly mediated by CYP2D613, 14,17,19), and several CYPs are involved in the N-demethylation 15"6,1 8,19) Venkatakrishnan et al reported that nortiptyline, classified in the same TCA group as amoxapine, is metabolized to 10-hydroxynortriptyline by CYP2D6 with an apparent Km value of 2.1 pM and CYP3A4 with an apparent Km value of 37.4 pM13).…”