Archiv der Pharmazie (Weinheim) 1998-04-01

7-Aminocoumarins are substrates of cytochrome P450-isozymes.

M Tegtmeier, W Legrum

Index: Arch. Pharm. (Weinheim) 331 , 143-148, (1998)

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Abstract

N-Alkyl-7-aminocoumarins are dealkylated by murine cytochrome P450. There are differences between the N-dealkylation of secondary and tertiary amines. 7-Ethylamino-4-methylcoumarin is deethylated by isozymes induced by 3-methylcholanthrene, in contrast to 7-diethylamino-4-methylcoumarin and 7-diethyl-amino-4-trifluoromethylcoumarin, which are deethylated mostly by isozymes induced by phenobarbital. Although the deethylation of the secondary amine can be increased also by a pretreatment with pyrazole, a specific inducer of the coumarin 7-hydroxylase (CYP2A5), there is no specific affinity for this isozyme. This result is supported by the second specific inducer of CYP2A5 cobalt, because cobalt did not influence the deethylation of 7-ethylamino-4-methylcoumarin. In addition, it was shown that (in contrast to earlier investigations) pyrazole beside CYP2A5 also induces further cytochrome P450 isozymes. In series of four compounds, 7-ethylamino-4-methylcoumarin is the singular 7-aminocoumarin which is accepted as substrate by the coumarin 7-hydroxylase. In addition, the metabolism of the 7-aminocoumarins was investigated to look for further metabolic products. The most interesting result is the double deethylation of 7-diethylamino-4-methylcoumarin to the primary amine. In the scope of the studies the advantages of new calculating structure-activity-relationships (QSAR-plot) could also be demonstrated.