5721-37-9Relevant articles and documents
Cytochrome P-450 enzymes contributing to demethylation of maprotiline in man
Brachtendorf, Lars,Jetter, Alexander,Beckurts, K. Tobias,Hoelscher, Arnulf H.,Fuhr, Uwe
, p. 144 - 149 (2007/10/03)
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 μM). For selective inhibition of CYPs, quinidine (0.5-50 μM; CYP2D6), furafylline (0.3-30 μM; CYP1A2), ketoconazole (0.2-20 μM; CYP3A4), mephenytoin (20-200 μM; CYP2C19), chlorzoxazone (1-100 μM; CYP2E1), sulphaphenazole (0.2-100 μM; CYP2C9) and coumarin (0.2-100 μM; 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 (KM=71 and 84 μM) and a low (KM=531 and 426 μM) affinity site for maprotiline in the two samples, respectively. The high affinity site was competitively inhibited by quinidine (Ki,c 0.13 and 0.61 μM), the low-affinity site was non-competitively inhibited by furafylline (Ki,nc 0.11 and 1.3 μM). Thus it appears that CYP2D6 and CYP1A2 contribute to maprotiline demethylation. Based on the parameters obtained, for plasma concentrations of 1 μM 83% (mean) of desmethylmaprotiline formation in vivo is expected to be mediated by CYP2D6 while 17% only may be attributed to CYP1A2 activity.
