Assessments of <scp>CYP</scp>‐Inhibition‐Based Drug–Drug Interactions Between Tofacitinib and Lipid‐Lowering Agents in Rats Both In Vitro and In Vivo

Tofacitinib is a widely used medication for the treatment of arthritis. It has been reported that some patients experience abnormal cholesterol levels following treatment, leading to recommendations for the coadministration of lipid-lowering drugs such as statins. In this study, we investigated the potential drug-drug interactions between tofacitinib and the statins simvastatin and lovastatin. In the in vitro experiments, rat liver microsomes were employed to evaluate the inhibitory effects of lipid-lowering agents on the metabolism of tofacitinib, with the primary metabolite M8 analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. The results showed that simvastatin and lovastatin significantly inhibited the metabolism of tofacitinib, with IC₅₀ values of 5.837 and 10.68 μM, respectively. For the in vivo pharmacokinetic studies, Sprague-Dawley rats were pretreated with simvastatin or lovastatin via oral gavage for 7 days before the oral gavage of tofacitinib. This pretreatment led to an increased area under the concentration-time curve of tofacitinib, suggesting that a potential reduction in the first metabolism and/or systemic clearance takes place. These findings demonstrate significant interactions between tofacitinib and certain lipid-lowering agents in the rat model, particularly simvastatin and lovastatin, both in vitro and in vivo.