TABLE 4

Gut-specific cutoffs or criteria for natural product–drug interactions

Cutoffs or criteria used in decision tree for physiologically-based pharmacokinetic modeling of natural product–drug interactions depicted in Fig. 3. For additional information or for cutoff values related to other organ systems, refer to (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf; FDA, 2020).

Transporter Inhibition
P-gp and BCRP(Dose/250 ml)/Ki,u (or IC50,u) ≥ 10
Enzyme Inhibition
Reversible InhibitionTime-Dependent Inhibition
CYP3A(Dose/250 ml)/Ki,u ≥ 10kobs/kdeg ≥ 10, wherein kobs = (kinact ⋅ Dose/250 ml)/(KI,u + Dose/250 ml)
CYP Inductiona
1. Concentration-dependent increase in mRNA expression of a CYP
2. ≥ 2-Fold increase of CYP mRNA expression relative to vehicle control at expected gut drug concentrations
3. Increase ≥20% of the positive control response