Effect of a Combination of Berberine and Monacolin on CYP Enzymes: An Oral Cocktail Interaction Study in Healthy Volunteers

Objectives: This study was aimed at investigating the potential of the herbal exctracts, berberine and monacolin, administered in combination at the recommended dose, to generate clinically relevant inhibition of the CYP (cytochromes P450) enzyme system after a single oral administration in human healthy volunteers. Methods: Twelve healthy male volunteers received a five-probe drug cocktail alone (reference) or with the combination of berberine and monacolin (test), in a randomized, open label, crossover fashion. Plasma concentrations of cocktail components, caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4), warfarin (CYP2C9), and plasma concentrations of berberine, monacolin and its metabolite were measured by LC-MS/MS. Pharmacokinetic parameters were determined by non-compartmental analysis. Lack of inhibition was assumed if the 90% CI (confidence interval) for estimated ratio test/reference was included in the acceptance limits 0.70-1.43 for phenotyping metrics AUClast and Cmax. Key findings: All test/reference ratios were close to unity and CIs (confidence intervals) were within the acceptance limits, except for the upper value of omeprazole Cmax. Given the high intraindividual variability, this finding was considered clinically irrelevant. Conclusions: Clinically relevant inhibition of the activities of the CYP isoenzymes investigated can be excluded when berberine and monacolin are administered in combination at the recommended dose.