Herb-Drug Interaction Between Sailuotong and Pitavastatin: A Systematic Pharmacokinetic Investigation and Mechanism...

Sailuotong (SLT), a standardized Chinese herbal preparation for vascular dementia (VaD), is frequently co-administered with pitavastatin (PIV). Potential herb-drug interactions (HDIs) between these agents remain uncharacterized. Given the high likelihood of using this combination to treat VaD, this study aims to systematically evaluate the effects of SLT on PIV's pharmacokinetics and elucidate underlying mechanisms.

Rats received single or repeated doses of SLT followed by oral or intravenous PIV. Plasma and hepatic PIV concentrations were quantified via LC-MS/MS. Biliary excretion and enterohepatic circulation interruption models assessed elimination pathways. The expression of hepatic and intestinal transporters was analyzed by RT-PCR and Western blot. Transporter functionality was validated using MDR1 substrates (digoxin and betrixaban).

Single-dose SLT increased PIV's C_max and AUC_0-9h by approximately 23.30% and 15.70%, respectively. Repeated SLT administration significantly decreased PIV's AUC by 32.90%, and reduced its hepatic accumulation by 68.96%. Intravenous studies revealed that SLT primarily affected the later exposure phases. Multiple doses of SLT decreased PIV's total biliary excretion by 33.10%. Mechanistically, SLT significantly induced the expression of MDR1 mRNA and proteins in the intestine and liver, and MRP2 in the liver. Additionally, SLT significantly decreased the exposure levels of digoxin and betrixaban, with betrixaban's C_max and AUC remarkably reduced by 86.44% and 79.74%, respectively.

Combining SLT and PIV can lead to HDIs, with multiple doses of SLT significantly reducing the plasma and hepatic exposure of PIV in rats. The primary mechanism appears to be the induction of the intestinal efflux transporter MDR1, resulting in decreased bioavailability of PIV.