Pharmacokinetic changes of nintedanib in collagen-induced arthritic rats are related to reduction of intestinal P-glycoprotein expression.

Rheumatoid arthritis (RA) patients often develop comorbid RA-associated interstitial lung disease, which is a severe extra-articular manifestation associated with high incidence and mortality rates. Nintedanib, an oral small-molecule tyrosine kinase inhibitor, has shown promise in clinical studies by mitigating disease progression and enhancing lung function among RA-associated interstitial lung disease patients. Adverse reactions to nintedanib are closely linked to its blood concentration, potentially leading to discontinuation due to gastrointestinal side effects and elevated liver enzymes. However, existing research has yet to delve into the pharmacokinetic impact of RA on nintedanib. Therefore, we established a collagen-induced arthritis rat model to examine how RA influences the pharmacokinetics of nintedanib. Additionally, we conducted Caco-2 transport experiments to explore potential factors contributing to these pharmacokinetic alterations. Our findings reveal that nintedanib's pharmacokinetics change in collagen-induced arthritic rats at different disease stages compared to the control group. This alteration results in a notable increase in blood drug concentration and significant changes in pharmacokinetic parameters such as maximum serum concentration (Cmax), AUC0-t, AUC0→∞, and time to reach peak concentration (Tmax). The outcomes from the Caco-2 transport experiments indicate that interleukin 6 stimulation impedes nintedanib efflux, aligning with the observed pharmacokinetic alterations. Further Western blot experiments suggest that the changes in nintedanib's pharmacokinetics are associated with reduced expression of P-glycoprotein. Moreover, our findings suggest that RA may reduce intestinal P-glycoprotein expression by activating the C-Jun N-terminal kinase signaling pathway. SIGNIFICANCE STATEMENT: Rheumatoid arthritis significantly increases the drug concentration of nintedanib. These data suggest that rheumatoid arthritis may be caused by reducing the expression of P-glycoprotein by affecting the C-Jun N-terminal kinase signaling pathway.