Common multiple interactions of tricyclic antidepressants and orphenadrine with liver microsomal cytochrome P450 enzymes of the rat

Abstract

1. Interactions of tricylic anti-depressants (TCA) and structurally related drugs with rat microsomal cytochromes P450 were studied including competitive inhibition of enzymatic activities and formation of P450 metabolite complexes. 2. All compounds examined that carry a methylated aminoalkyl sidechain formed metabolite complexes with microsomal P450 of the untreated male rat. The extent of complex formation is only slightly altered by rat pre-treatment with P450 inducers indicating that mainly constitutive P450 enzymes are involved. 3. The kinetics of in vitro complex formation differed for the di- and monomethylamino derivatives of the TCA showing either a sigmoidal or hyperbolic shape respectively. Considerable auto-inhibition of complex formation is observed at concentrations 100 muM only with the dimethyl derivatives. 4. Besides metabolite complex formation, a further effect of the drugs is competitive inhibition of the CYP2B-dependent pentoxyresorufin O-dealkylation. The inhibitory potential of the drugs depends on their degree of N-alkyl substitution. Correspondingly, the Ki is in the range of 2.8-7.1, 0.1-0.2 and 0.01 muM for the dimethyl-, monomethyl- and unsubstituted drugs respectively. 5. It has been shown that P450 interactions with tricyclic anti-depressants include several types of mechanisms and several P450 enzymes. It might be pharmacologically important that the dimethylamino compounds are demethylated in vivo by cytochromes P450 giving rise to more potent P450 inhibitors compared with the parent compounds.