Drug-Drug Interaction Potential Of 1,5-Dicaffeylquinic Acid, A New Herbal Drug For The Treatment Of Hepatitis B And Human Immunodeficiency Virus Infection, Based On The Inhibition Of Cytochrome P450s In Human And Rat Liver Microsomes

The inhibition of cytochrome P450s (CYPs) is regarded as one of the most important causes for drug-drug interactions. 1,5-Dicaffeylquinic acid (1,5-DCQA) is currently being evaluated in a phase II clinical study in China for the treatment of hepatitis B and human immunodeficiency virus infections. The purpose of this study was to investigate the in vitro inhibitory effect of 1,5-DCQA on six major CYP enzymes to assess its safety through its potential to interact with co-administered drugs. Seven CYP probe substrate metabolites (acetaminophen for CYP1A2, 6 alpha-hydroxypaclitaxel for CYP2C8, 4-hydroxydiclofenac for CYP2C9, 4-hydroxymephenytoin for CYP2C19, dextrorphan for CYP2D6, and 6 beta-hydroxytestosterone and 1-hydroxymidazolam for CYP3A4) were measured simultaneously by LC-MS/ MS. 1,5-DCQA was incubated with human and rat liver microsomes in the presence of seven CYP450 isoform substrates, and the in vitro inhibitory effects were evaluated by determining the IC50 values. 1,5-DCQA showed negligible inhibitory effects on the six major human (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and rat CYP isozymes (Cyp1a2, Cyp2c7, Cyp2c11, Cyp2c79, Cyp2d4, and Cyp3a2). All IC50 values exceeded 100 mu M. Our study demonstrates that 1,5-DCQA is unlikely to cause significant drug-drug interactions in humans when co-administered with drugs metabolized by the six CYP isozymes.