Investigate The Absorption Mechanisms Of LLDT-8and The Drug-Drug Interactions With Methotrexate

Rheumatoid arthritis is a common and intractable chronic systemic autoimmune disease. Most immunosuppressive agents lack specificity and selectivity on the immune system, so the toxic side effects limited them to be widely used.(5R)-5-hydroxytriptolide (LLDT-8) is a first-class original new drug treating Rheumatoid arthritis by Shanghai Pharmaceutical Group Co. Ltd. It will be used to treat rheumatoid arthritis in clinical in combination with methotrexate. This study is to investigate the metabolism mechanisms of LLDT-8.LLDT-8has high permeability. The papp of different concentrations is not obvious, and there is a linear relationship with the increase of concentration.LLDT-8has a higher absorption in rat duodenum, jejunum, ileum and colon. After giving Methotrexate, absorption rate of LLDT-8declined slightly in the intestine except duodenum. The result shows that the LLDT-8group has no significant difference between LLDT-8-Methotrexate combination group.LLDT-8is neither a direct inhibitor nor time-dependent inhibitor of above five CYPs, and LLDT-8did not induce major CYPs in cryopreserved human hepatocyte, which tested at a concentration range of0.1to10μM. The potential of drug-drug interaction caused by LLDT-8inhibition or induce on CYP450isozymes is slim.LLDT-8is neither a substrate nor an inhibitor of P-gp, and its potential of drug-drug interaction with P-gp substrates or inhibitors is very low via MDCK-MDR1cell model. However, LLDT-8is not a substrate for BCRP, but it has some inhibitory via Caco-2cell model.Generally speaking, LLDT-8is well absorbed. It seems impossible that LLDT-8has a drug-drug interactions with methotrexate, and the results can be used as a theoretical support for clinical treatment.