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 （CYP2C 19）, 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.

Effect of food on the Oral Bioavailability of Berberine and Monacolin Administered in Combination in Healthy Male Volunteers

Objectives： To investigate the effect of food on the bioavailability of a combination of monacolin and berberine in healthy volunteers. Methods： Eighteen male volunteers received a single recommended oral dose of the combination under fasted conditions （reference） and fed conditions （high fat meal; test）, in a randomized, open label, crossover fashion. Plasma concentrations of berberine, monacolin and its metabolite were measured by LC-MS/MS. Pharmacokinetic parameters were determined by non-compartmental analysis. No effect of food was assumed if the 90% CIs （confidence intervals） for estimated ratio test/reference was included in the acceptance limits 0.80-1.25 for phenotyping metrics AUCt and Cmax- Key findings： For berberine, the Cmax and AUCt test/reference ratios were 2.97 and 2.69, respectively, and relevant 90% CIs （2.25-3.91 and 2.15-3.36, respectively） were above the acceptance limit. For lovastatin hydroxy acid, the active metabolite of monacolin, the test/reference ratios were 1.18 （Cmax） and 0.98 （ALJCt）. The 90% CIs fell entirely within the acceptance limit for AUCt, （0.85-1.13）, whereas the upper bound of the 90% CIs for Cmax （1.01-1.37） was just above the predefined interval. Conclusions： Food intake significantly increases berberine bioavailability and does not significantly affect monacolin bioavailability when these two extracts are administered in combination.