Mechanism-Based Inhibition of Human Liver Microsomal Cytochrome P450 2D6 (CYP2D6) by Alkamides of Piper nigrum

Abstract

Nineteen alkamides isolated from Piper nigrum L. were tested for their mechanism-based inhibition on human liver microsomal dextromethorphan O-demethylation activity, a prototype marker for cytochrome P450 2D6 (CYP2D6). All compounds increased their inhibitory activity with increasing preincubation time. Among them, 15 and 17 showed more than 50 % decrease of the CYP2D6 residual activity after 20 min preincubation. Further investigations on 15 and 17 showed that the characteristic time- and concentration-dependent inhibition, which required a catalytic step with NADPH, was not protected by nucleophiles, and was decreased by the presence of a competitive inhibitor. The kinetic parameters for inactivation (k _inact and K _I) were 0.028 min^-1 and 0.23 μM for 15 and 0.064 min^-1 and 0.71 μM for 17, respectively, which were stronger than the known mechanism-based inhibitor, paroxetine (a positive control). Thus, 15 and 17 are potent mechanism-based inhibitors of CYP2D6.

Key words

Piper nigrum - alkamides - cytochrome P450 2D6 - CYP2D6 - mechanism-based inhibition - drug-herb interaction

References

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