Labeled content of two furanocoumarins in dietary supplements correlates with neither actual content nor CYP3A inhibitory activity

Abstract

Dietary supplements are a multi-billion dollar business, with yearly profit increases. Allegedly safe, these supplements are marketed to a variety of niches, encompassing claims from immune support to weight loss. Six sports nutrition supplements were acquired that were labeled to contain the furanocoumarin(s) bergamottin and/or 6′,7′-dihydroxybergamottin (DHB), both of which are potent irreversible inhibitors of the prominent drug metabolizing enzyme cytochrome P450 3A (CYP3A). Both furanocoumarins are typically present in grapefruit juice, which has been shown to inhibit intestinal CYP3A, perpetrating an increase in the systemic exposure of certain concomitant ‘victim’ drugs. The acquired supplements were analyzed using ultra-performance liquid chromatography coupled to both a photodiode array (PDA) detector and a triple quadrupole mass spectrometer (MS). Contrary to the product labeling, four of the supplements contained no detectable quantities of either furanocoumarin (LOD 0.060 μg/capsule), while two of the supplements contained minimal amounts (one contained 12.13 (± 0.23) μg bergamottin and 65.51 (± 0.64) μg DHB per capsule; the other contained 2.705 (± 0.069) μg bergamottin per capsule and no detectable quantities of DHB). A CYP3A inhibition bioassay was used to assess whether the actual content of the furanocoumarins correlated with CYP3A inhibitory activity. Despite the low amounts of bergamottin and DHB, CYP3A inhibition by the supplements was greater than could be accounted for by the two furanocoumarins. The additional activity suggests the presence of other potent or highly abundant CYP3A inhibitors.

Botanical Sources, Chemistry, Analysis, and Biological Activity of Furanocoumarins of Pharmaceutical Interest

“…Given the increasing relevance of synergistic effects in plant material used for health purposes and according to our increased capability of managing and decoding large datasets, metabolomic evaluations could be used more frequently also in combination with bioactivity assays. The recourse to metabolomics is to be considered relevant also from a toxicological standpoint, as intense CYP450 inhibitions have been reported, for instance, in food supplements also in the absence of most common furanocoumarins [153].…”

Effect of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

“…Generally, xanthotoxin may be considered as a substrate isolated from plants and medicinal herbs, which due to chemical modifications may gain some novel properties and indications for the clinical use. Of note, some bioactive compounds of natural origin can be readily isolated from plants and medicinal herbs, purified, concentrated and applied either as drugs or dietary supplements to cure various diseases or to support the healthy lifestyle [43,44].…”

Selection and characterization of botanical natural products for research studies: a NaPDI center recommended approach

“…One technique is to conduct a "spike recovery" study, in which a standard is spiked into the botanical matrix at known concentrations, and the concentration is backcalculated to evaluate accuracy. 95,[196][197][198] Quantitative NMR and pre-or post-column derivatization 199 also can be used to quantify metabolites without known standards. 200 We end this section with a word of caution, which is that it is easy to become so focused on method validation that one is distracted from the overall research question (which typically relates to safety and/or efficacy of a botanical).…”