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Introduction: In clinical practice, warfarin is often combined with Compound Danshen dripping pill (CDDP) for the treatment of cardiovascular diseases. However, warfarin has a narrow therapeutic index, wide interindividual variability (genetic and non-genetic factors), and is susceptible to drug-drug interactions. Our previous study indicated that CDDP might interact with warfarin in individuals with the epoxide hydrolase gene (EPHX1; single-nucleotide polymorphism: rs2292566) A/A subtype. We sought to clarify the interaction between CDDP and warfarin associated with EPHX1 in a comprehensive and accurate manner. Methods: Here, EPHX1 A and EPHX1 G cell lines were established. Expression of microsomal epoxide hydrolase (mEH), vitamin K epoxide reductase (VKOR), and vitamin K-dependent clotting factors (FII, FVII, FIX, FX) was measured by western blotting upon incubation with CDDP and warfarin. mEH activity was evaluated by measuring the transformation of epoxyeicosatrienoic acids into dihydroxyeicosatrienoic acids. Then, healthy volunteers (HVs) with the EPHX1 A/A genotype were recruited and administered warfarin and CDDP to investigate the pharmacokinetics and pharmacodynamics of warfarin. Results: CDDP combined with warfarin could decrease expression of mEH and VKOR, and increase protein expression of FII, FVII, FIX, and FX, in EPHX1 A cells. CDDP could slightly influence the pharmacokinetics/pharmacodynamics of warfarin in HVs with the EPHX1 A/A genotype. Discussion: Rational combination of CDDP and warfarin was safe with no risk of bleeding, but the therapeutic management is also needed. The clinical study is posted in the China Clinical Trial Registry (ChiCTR190002434).
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Background: Combination of Polygonum capitatum Buch.-Ham. ex D. Don extract (PCE) and ciprofloxacin (CIP) was commonly prescribed in the treatment of urinary tract infections. Their pharmacokinetic herb-drug interactions (HDIs) were focused in this study to assess potential impact on the safety and effectiveness. Methods: A randomized, three-period, crossover trial was designed to study the pharmacokinetic HDI between PCE and CIP in healthy humans. Their pharmacokinetic- and tissue distribution-based HDIs were also evaluated in rats. Gallic acid (GA) and protocatechuic acid (PCA) were chosen as PK-markers of PCE in humans and rats. Potential drug interaction mechanisms were revealed by assessing the effects of PCE on the activity and expression of multiple transporters, including OAT1/3, OCT2, MDR1, and BCRP. Results: Concurrent use of PCE substantially reduced circulating CIP (approximately 40%-50%) in humans and rats, while CIP hardly changed circulating GA and PCA. PCE significantly increased the tissue distribution of CIP in the prostate and testis of rats, but decreased in liver and lungs. Meanwhile, CIP significantly increased the tissue distribution of GA or PCA in the prostate and testis of rats, but decreased in kidney and heart. In the transporter-mediated in vitro HDI, GA and PCA presented inhibitory effects on OAT1/3 and inductive effects on MDR1 and BCRP. Conclusion: Multiple transporter-mediated HDI contributes to effects of PCE on the reduced systemic exposure and altered tissue distribution of CIP. More attention should be paid on the potential for PCE-perpetrated interactions.
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ETHNOPHARMACOLOGY RELEVANCE: Polygonum capitatum Buch-Ham. ex D. Don (CNPC2009), a traditional Miao-national herbal medicine, has been widely used with considerable therapeutic efficacy in the treatment of various urologic disorders including prostatitis. However, the molecular mechanism of action (MOA) remains unclear. AIM OF THE STUDY: In this study, UPLC-Q-Exactive-MS and Network pharmacological methods were used to explore the underlying molecular MOA of Polygonum capitatum Buch-Ham. Ex D. Don (P.capitatum) for the treatment bacterial prostatitis (BP). MATERIALS AND METHODS: The UPLC-Q-Exactive-MS technique was used to identify the chemical components of P. capitatum. Databases such as SwissTargetPrediction, Gene Cards, and OMIM were used to predict the targets of P. capitatum for the treatment of BP. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to analyze the protein-protein interaction (PPI) and construct a PPI network, and the Metascape was used for Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. In addition, experimental treatment of Escherichia coli (E.coli)-induced BP was verified. RESULTS: A total of 31 molecular components were identified by UPLC-Q-Exactive-MS. Network pharmacology revealed that P. capitatum may act on the AKT1, PI3K, MTO, EGFR and other targets through active components such as Gallic acid, Quercetin, Luteolin, Protocatechuic Acid, Kaempferol and thereby regulate PI3K-AKT, ErbB, AMPK, HIF-1, and other signaling pathways to intervene in the pathological mechanism of BP. Verification through experimental results showed that compared with the model group, treatment with P. capitatum could significantly inhibit bacterial growth in prostate tissues, lowered the prostate index, down-regulated the levels of inflammatory mediators(IL-1ß, IL-6, and TNF-α) in prostate tissues, and down-regulate the protein expression and mRNA expression levels of AKT and PI3K. CONCLUSION: This study preliminarily revealed the MOA of P. capitatum for treating BP with multiple components, multiple targets, and multiple pathways, especially affecting the PI3K-AKT signaling pathways.
