TABLE 3

Examples of natural product–drug interactions predicted using static and PBPK models

Natural ProductObject Drug(s)Biochemical Target(s)Model TypeChange in Object-Drug AUC or R2Reference(s)
Common NameLatin NamePrecipitant Constituent(s)PredictedObserved
Cannabis, marijuanaCannabis sativa L.CBD, THCPhenacetin, diclofenac, omeprazole, dextromethorphan, testosteroneCYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3AStaticCBD: >5-fold ↑ for CYP2C19 and CYP3A substrates; THC: >5-fold ↑ for CYP2C9 substratesNRBansal et al. (2020)
CinnamonCinnamomum spp.trans-Cinnamic aldehydeLetrozole, nicotineCYP2A6Static1.1- to 3.6-fold ↑NRChan et al. (2016)
trans-Cinnamic aldehyde, 2-methoxycinnamaldehyde∼4- to 5-fold ↑Espiritu et al. (2020)
Curcumin (as a solid lipid nanoparticle)Curcuma longa L.Curcumin, curcumin glucuronideImatinib, bosutinib, paclitaxelCYP2C8, CYP3A4PBPK≤1.10-Fold ↑ for imatinib and bosutinibNRAdiwidjaja et al. (2020a)
GoldensealHydrastis canadensis L.Berberine, (-)-β-hydrastine, hydrastinineDextromethorphan, midazolam, diclofenacCYP2C9, CYP2D6, CYP3AStaticR2 = 1.00, 7.90, and 1.26 for berberine and CYP2C9, CYP2D6, and CYP3A4, respectively; R2 = 8.94, ∼4, and 17.8 for (-)-β-hydrastine and CYP2C9, CYP2D6, and CYP3A4, respectivelyNR for dextromethorphana 1.62-fold ↑ for midazolam after 2 wk of goldenseal administration (1323 mg three times daily) NR for diclofenacGurley et al., (2008); Guo et al. (2012); McDonald et al. (2020)
Grapefruit juiceCitrus × paradisi Macfad.6′,7′-Dihydroxy-bergamottinLoperamideCYP3AStatic1.6-Fold ↑1.7-fold ↑Ainslie et al. (2014)
Green teaCamellia sinensis (L.) KuntzeECG, EGCGRaloxifeneUGTsStatic6.1- and 1.3-fold ↑, respectively, based on estimated concentrations in intestinal lumen and enterocyte30% ↓Tian et al. (2018b); Judson et al. (2020)
KratomMitragyna speciosa (Korth.) Havil.MitragynineDiclofenac, dextromethorphan, midazolamCYP2C9, CYP2D6, CYP3AStatic1.1- and 5.7-fold ↑ for dextromethorphan and midazolam, respectivelyNRTanna et al. (2020)
St. John’s wortHypericum perforatum L.HyperforinbAlprazolam, carbamazepine, docetaxel, ethinyl estradiol, imatinib, midazolam, tacrolimus, verapamil, zolpidem, ibuprofen, tolbutamide, S-warfarin, clopidogrel, omeprazoleCYP2C19, CYP2C9, CYP3APBPK2%–79% ↓ for all substrates except clopidogrel (1.31-fold ↑) and S-warfarin (1.06-fold ↑).Close agreement with observed changes (18%–23% difference)Adiwidjaja et al. (2019)
SilibininbSilybum marianum (L.) gaertn.Silybin A, silybin BMidazolam, warfarinCYP3A, CYP2C9PBPK1.05- and 1.04-fold ↑ for midazolam and S-warfarin, respectively1.09 and 1.13-fold ↑ for midazolam and S-warfarin, respectivelyBrantley et al. (2014b)
SilymarinSilybum marianum (L.) gaertn.Silybin A, silybin B, isosilybin A, isosilybin B, silychristinMidazolamCYP3AStatic1.75-fold ↑NRBrantley et al. (2013)
SilibininSilybum marianum (L.) gaertn.Silybin A, silybin BRaloxifeneUGTsPBPKUp to 1.3-fold ↑1.09-fold ↑Gufford et al. (2015a)
Silibinin, silymarinNA, Silybum marianum (L.) gaertn.Silybin A, silybin BRaloxifeneUGT1A1, UGT1A8, UGT1A10Static4- to 5-fold ↑ by silibinin and silymarin, respectively1.09-fold ↑Gufford et al. (2015a,b)
  • CBD, cannabidiol; CYP, cytochrome P450; EGCG, epigallocatechin gallate; NA, not applicable; NR, not reported; R2, intrinsic clearance ratio (without:with a time-dependent inhibitor); THC, tetrahydrocannabinol; UGT, UDP-glucuronosyltransferase.

  • a 9-Fold ↑ in urinary dextromethorphan:dextrorphan after 2 wk of goldenseal administration (300 mg three times daily).

  • b Semipurified extract of milk thistle containing silybin A and silybin B in approximately an equimolar ratio.