Mechanism-Based Inhibition of CYP3A Subfamilies by Macrolide Antibiotics and Piperine

Objective: The mechanism-based inhibition of macrolide antibiotics, such as erythromycin and clarithromycin, and piperine on testosterone 6β-hydroxylation activities by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared. Methods: 6β-Hydroxy testosterone was determined by high-performance liquid chromatography. Results: Although preincubation with erythromycin and clarithromycin decreased CYP3A4- mediated testosterone 6β- hydroxylation in a time-dependent manner, and the estimated maximum inactivation rate constant (k inact) and the inactivation rate constant reaching half of k inact (K i) for erythromycin were approximately 1/2 and 1/5, respectively, of those for clarithromycin. Obvious preincubation time-dependent inhibition of erythromycin against CYP3A5 and CYP3A7 was not observed. Piperine exhibited preincubation time-dependent inhibition and the calculated K i and k inact values for CYP3A4 were approximately 1/7 and 1/2, respectively, of those for CYP3A5. Conclusion: It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.