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 Inhibition	Time-Dependent Inhibition
CYP3A	(Dose/250 ml)/Ki,u ≥ 10	kobs/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

BCRP, breast cancer resistance protein; CYP, cytochrome P450; IC_50,u, unbound IC₅₀; k_deg, degradation rate constant; K_i,u, unbound reversible inhibition constant; k_obs, inactivation rate constant (observed); P-gp, P-glycoprotein.

^aMust satisfy all three criteria to qualify as a CYP inducer. Criteria are based on those recommended for hepatic CYP induction (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf; FDA, 2020).