A herb-drug interaction: The role of transporters in the modulation of atorvastatin absorption by Compound Danshen Tablets.

This study characterized the pharmacokinetic interaction between Compound Danshen Tablets (CDT) and atorvastatin (ATV) and investigated absorption- and transporter-related mechanisms underlying this interaction. ATV pharmacokinetics were evaluated after oral and intravenous administration in normal and hyperlipidemic/diabetic rats, with or without repeated CDT treatment. Mechanistic studies included single-pass intestinal perfusion, Caco-2 bidirectional transport assays, human multidrug resistance protein 1 inside-out vesicle transport assays, ileal P-glycoprotein (P-gp) immunoblotting, an in vivo digoxin probe-substrate experiment, and molecular docking. Repeated CDT administration increased oral ATV exposure in both normal and model rats, with the area under the plasma concentration-time curve from 0 to 24 hours and maximum plasma concentration increasing by up to 85.83% and 306.53%, respectively, whereas intravenous ATV pharmacokinetics were not significantly altered. In Caco-2 monolayers, ATV exhibited marked directional efflux, with an efflux ratio of 39.32, which was reduced to 10.99 by verapamil. CDT increased the apical-to-basolateral apparent permeability coefficient of ATV from 0.41 to 1.31 × 10-6 cm/s and reduced the efflux ratio to 9.82, whereas the basolateral-to-apical apparent permeability coefficient decreased from 16.27 to 12.90 × 10-6 cm/s. In human multidrug resistance protein 1 inside-out vesicles, CDT concentration dependently reduced ATP-dependent N-methylquinidine transport, with inhibition rates ranging from 24.97% to 80.45% at 50-800 μg/mL. Together with the ileal P-gp protein data and the digoxin probe-substrate experiment, these findings indicate that CDT enhances intestinal absorption of ATV primarily by attenuating intestinal P-gp-mediated efflux through reducing both P-gp transport activity and protein abundance. These results provide mechanistic evidence that modulation of intestinal efflux transport contributes to the increased systemic exposure of ATV after repeated CDT administration. SIGNIFICANT STATEMENT: This study identifies a clinically relevant herb-drug interaction in which repeated administration of compound Danshen tablets increases oral atorvastatin exposure in normal and hyperlipidemic/diabetic rats without materially altering intravenous atorvastatin pharmacokinetics. Integrated pharmacokinetic, single-pass intestinal perfusion, Caco-2 transport, human multidrug resistance protein 1 vesicle, ileal P-glycoprotein, and digoxin probe-substrate data support attenuation of intestinal P-glycoprotein-mediated efflux, through reduced transporter activity and protein abundance, as a mechanism enhancing atorvastatin absorption.