Considerable evidence from both in vitro and animal studies suggests that CYP2D6 activity can be inhibited by goldenseal [59
], milk thistle [61
], kava kava [59
], and St. John's wort [59
]. Currently, no in vitro results are available for black cohosh's effect on CYP2D6, although certain triterpene glycosides isolated from black cohosh modestly inhibited human CYP3A4 in vitro [69
]. However, evidence of in vitro CYP450 inhibition, or that observed in animal models, may not accurately predict in vivo effects observed in humans [70
]. Our purpose in this series of clinical studies was to assess whether botanical supplement formulations containing either goldenseal, milk thistle, kava kava, Echinacea
, St. John's wort, or black cohosh could modulate human CYP2D6 activity using standard phenotyping techniques.
Five of the botanicals evaluated in these 3 studies exerted no significant effects on CYP2D6 activity as determined by DURR. These included milk thistle, kava kava, Echinacea
, black cohosh and St. John's wort. Our clinical findings run counter to many of the in vitro predictions of CYP2D6 inhibition by these supplements [59
]. Significant divergence between in vitro predictions and in vivo realities are not uncommon. Reasons for such in vivo/in vitro discrepancies have been discussed in detail by von Moltke [70
], but certain other basic pharmaceutics issues relevant to dietary supplements may also contribute; these include poor dissolution characteristics of botanical formulations and significant inter-product variability in phytochemical content [52
]. Still other considerations include extensive pre-systemic in vivo conjugation of phytochemicals via Phase II enzymes (e.g. glucuronidation, sulfation, glycination), a process that may preclude CYP inhibition by these compounds [75
]. Nevertheless, our results confirm previous clinical findings that milk thistle [39
], kava kava [76
], black cohosh [39
], and St. John's wort [29
] are not potent modulators of human CYP2D6 in vivo. Several of the clinical studies involving St. John's wort, however, utilized dextromethorphan/dextrorphan urinary ratios as a phenotypic measure of CYP2D6 activity [29
], and this particular approach has been recently called into question [46
]. This uncertainty stems from the fact that normal physiological changes in urine pH can alter the dextromethorphan/dextrorphan ratio by as much as 20-fold [77
]. DURR, however, is not affected by urine pH and thus appears to be a more reliable phenotypic measure of CYP2D6 activity [46
]. Collectively, these studies, particularly those using DURR, strongly suggest that these 5 botanicals pose little to no significant concerns regarding pharmacokinetic herb-drug interactions with drugs metabolized by CYP2D6.
Of the 6 botanical extracts evaluated in this series of clinical studies, only goldenseal appeared to have significant inhibitory effects on human CYP2D6 in vivo. The almost 50% reduction in mean post-supplementation DURR signifies that goldenseal is a potent inhibitor of human CYP2D6 in vivo. Moreover, these results corroborate an earlier report by our group, which utilized a different goldenseal formulation [76
]. Our findings also bolster recent in vitro investigations demonstrating inhibition of CYP2D6-mediated biotransformations by goldenseal extracts [59
]. During an evaluation of a series of single-entity herbal tea extracts, Foster et al observed that Hydrastis canadensis
(goldenseal) produced the greatest percent inhibition of cDNA expressed human CYP2D6 [59
]. In addition, Chatterjee and Franklin observed that goldenseal extract and its principal isoquinoline alkaloids, berberine and hydrastine, inhibited CYP2D6-mediated bufuralol 1'-hydroxylation in human hepatic microsomes [60
]. Of the two alkaloids, berberine exhibited a greater effect on bufuralol 1'-hydroxylation (IC50
= 45 μM) than hydrastine (IC50
= 350 μM), signifying a greater contribution of this phytochemical to CYP2D6 inhibition.
At present, little is known about the pharmacokinetics of goldenseal alkaloids in humans, but animal studies indicate that berberine bioavailablity is relatively low [79
]. Although the daily dose of isoquinoline alkaloids ingested in the present study was 209 mg (), plasma concentrations of berberine and hydrastine were not determined; nevertheless, the significant effect observed on CYP2D6 phenotype indicates that phytochemicals present in goldenseal can cross the intestinal mucosa. Taken together, both in vitro and in vivo findings imply that goldenseal, if taken concomitantly with CYP2D6 substrates, may give rise to clinically significant herb-drug interactions.
In summary, the data presented herein supports previous clinical investigations that milk thistle, kava kava, black cohosh, Echinacea, and St. John's wort are not potent modulators of human CYP2D6 in vivo. Thus, concomitant ingestion of these specific botanicals with drugs that are CYP2D6 substrates is not likely to result in clinically relevant herb-drug interactions. On the other hand, goldenseal significantly inhibits human CYP2D6 in vivo and may give rise to significant pharmacokinetic herb-drug interactions. Accordingly, patients should be strongly discouraged from taking goldenseal-containing supplements concomitantly with prescription medications, especially those extensively metabolized by CYP2D6.