Table 2.

In vitro-in vivo predictions of transporter-mediated goldenseal-drug interactions using established basic models for clinically relevant transporters per FDA guidance.

Transporter	Basic modela	Goldenseal Extract R-value	Predicted Effect
BCRP	$\text{R = }\frac{\text{Igut}}{\text{IC50}}\ge \text{10}$	601	↑ rosuvastatin AUC
MDR1		--	No interaction
OAT1	$\text{R = }\frac{\text{Imax,u}}{\text{IC50}}\ge 0..1$	<0.001	No interaction
OAT3		<0.001	No interaction
OCT2		<0.001	No interaction
MATE1		.002	No interaction
MATE2-K		0.002	No interaction
OATP1B1 OATP1B3	$\text{R}=1+\frac{\text{fu},\text{p}\times \text{Iin},\text{max}}{\text{IC}50}\ge 1.1$	1.5	↑ rosuvastatin AUC
		4.2	↑ rosuvastatin AUC

--, No interaction predicted based on low inhibition potential in transporter assay (IC₅₀ > 100 μM).

^aIC₅₀ values for the goldenseal extract, depicted in Table 1, were used in basic models.

I_gut, intestinal luminal concentration of inhibitor, estimated as the ratio of the mass of berberine (29.8 mg) in a 1-gram capsule of goldenseal to 250 mL. f_u,p, fraction unbound of inhibitor (berberine) in plasma, estimated to be 0.75 using GastroPlus version 9.7 (Simulations Plus, Lancaster, CA). I_max,u, maximum unbound plasma concentration of berberine at steady state, estimated as the product of f_u,p and the maximum reported plasma concentration of berberine (0.44 ng/mL),⁴⁹ adjusted to dose (0.033 ng/mL), and scaling to 0.20 ng/mL (0.59 nM) based on an accumulation ratio of 5.95, calculated using the equation 1/(1-e^−k*^T), where k and T are the elimination rate constant³² (0.023 h⁻¹) and dosing interval (8 h), respectively. For simplicity, a dosing interval of 8 h was used. I_in,max, estimated maximum plasma concentration of inhibitor (berberine) at the inlet of the liver, calculated as I_max + (F_a × F_g, × k_a × dose)/(Q_h/R_B), where F_a is the fraction of berberine absorbed after oral administration of a 1-gram capsule of goldenseal, F_g is the fraction of berberine that escapes intestinal metabolism, k_a is the first-order absorption rate constant for berberine, Q_h is hepatic blood flow (97 L/hr),⁵⁰ and R_b is the blood-to-plasma concentration ratio. Because the data were not available, F_a, F_g, and R_b were set to 1, and k_a was set to 0.1 min⁻¹ per FDA guidance.²⁴