Gemcitabine enhances pharmacokinetic exposure of the major components of Danggui Buxue Decoction in rat via the promotion of intestinal permeability and down-regulation of CYP3A for combination treatment of non-small cell lung cancer

• Published in: Pharmaceutical biology 2023-12, Vol.61 (1), p.1298-1309
• Main Authors: Xu, Xin, Sun, Xi-yang, Chang, Ming, Hu, Zhao-liang, Cheng, Ting-ting, Hang, Tai-jun, Song, Min
• Format: Article
• Language: English
• Subjects: Antitumor activity; bioavailability; Drug interaction; Ferulic acid; Gemcitabine; Glucose transporter; herb–drug interaction; Intestine; Liver; Lung cancer; metabolism; Non-small cell lung carcinoma; Permeability; Pharmacokinetics; Small cell lung carcinoma; Traditional Chinese medicine; Zonula occludens-1 protein
• ISSN: 1388-0209; 1744-5116
• DOI: 10.1080/13880209.2023.2246500

ContextDanggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine’s active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD’s major components remains unclear.ObjectiveThis study evaluates the herb–drug interaction between DBD’s major components and gemcitabine and validates the underlying pharmacokinetic mechanism.Materials and methodsThe pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis.ResultsThe combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD’s major components in rats. The Cmax and AUC of calycosin-7-O-β-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life (t1/2) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression.Discussion and conclusionsGemcitabine could modulate the pharmacokinetics of DBD’s major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.