Assessment of potential disease-drug interactions when prescribed Fuzi for rheumatoid arthritis treatment, with focus on the pharmacokinetics of aconitine, mesaconitine, and hypaconitine.

Abstract

Ethnopharmacological relevance: Fuzi is a toxic traditional Chinese medicine that is commonly prescribed for rheumatoid arthritis (RA), while CYP3A4 and P-gp are primarily responsible for the metabolism and efflux of its toxic alkaloids: aconitine (AC), mesaconitine (MA), and hypaconitine (HA). However, the RA condition may induce disease-drug interactions due to the elevated IL-6 and TNF-α levels, which significantly inhibit the function of CYPs and P-gp.

Aim of the study: To investigate the existence of disease-drug interactions during Fuzi treatment for RA, focusing on the pharmacokinetics of AC, MA, and HA.

Materials and methods: An RA model in DBA/1J mice was established using type II collagen, and the expression levels of Cyp3a11 and P-gp in mice were measured under RA conditions. Then, the pharmacokinetics and tissue distribution of AC, MA, and HA following the administration of HSP (the preparations of Fuzi) or pure alkaloids in both normal and RA model mice were investigated using UHPLC-MS/MS. At the same time, we measured the biomarkers indicative of Fuzi's cardiotoxicity in plasma after administering HSP or the individual monomers.

Results: In the developed collagen-induced arthritis (CIA) mouse model, we observed significant IL-6 and TNF-α elevation accompanied by reduced hepatic Cyp3a11 (human CYP3A4 homolog) and P-gp expression. Pharmacokinetic analysis revealed remarkable increases in the C_max and AUC_0-t values of AC, MA, and HA following oral administration of Fuzi preparations or pure alkaloids in CIA mice compared with controls. The accumulation of these alkaloids in the heart (the primary target for Fuzi's toxicity), as well as in the intestine, liver, and kidneys of CIA mice, was also significantly elevated. Furthermore, CIA mice exhibited markedly elevated levels of cardiotoxic markers, creatine kinase, and lactate dehydrogenase, which strongly correlated with the AUC_0-t values of AC, MA, and HA.

Conclusion: RA-induced cytokine dysregulation potentiates Fuzi's cardiotoxicity through CYP3A4/P-gp suppression-mediated pharmacokinetic alterations. Thus, caution should be exercised regarding the potential cardiotoxicity resulting from disease-drug interactions in RA patients undergoing treatment with Fuzi.