Role of Toll-like receptor 4 in drug-drug interaction between paclitaxel and irinotecan in vitro

- New mechanism of paclitaxel and Irinotecan drug-drug interaction is proposed.
- Paclitaxel activates Toll-like receptor 4 to alter drug metabolizing enzymes/transporters in hepatocytes.
- Activation of Toll-like receptor 4 by paclitaxel alters irinotecan pharmacokinetics in hepatocytes.
- Potential role of Toll-like receptors as novel modulators of drug-drug interactions

The bacterial receptor, Toll-like receptor (TLR) 4 mediates inflammatory responses and has been linked to a broad array of diseases. TLR4 agonists are being explored as potential treatments for cancer and other diseases. We have previously shown that activation of TLR4 by lipopolysaccharide (LPS) leads to down-regulation of drug metabolizing enzymes/transporters (DMETs), and altered pharmacokinetics/pharmacodynamics (PK/PD) of drugs. These changes can increase the risk of drug-drug interactions (DDIs) in patients on multiple medications. Clinically, DDI was observed for combination chemotherapy of paclitaxel (TLR4 ligand) and irinotecan. To determine the role of TLR4 in DDI between paclitaxel and irinotecan in vitro, primary hepatocytes from TLR4-wild-type (WT) and mutant mice were pre-treated with paclitaxel, followed by irinotecan. Gene expression of DMETs was determined. Paclitaxel treatment increased the levels of irinotecan metabolites, SN-38 and SN-38 glucuronide (SN-38G) in TLR4-dependent manner. Paclitaxel-mediated induction of genes involved in irinotecan metabolism such as Cyp3a11 and Ugt1a1 was TLR4-dependent, while induction of the transporter Mrp2 was TLR4-independent. These novel findings demonstrate that paclitaxel can affect irinotecan metabolism by a TLR4-dependent mechanism. This provides a new perspective towards evaluation of marketed drugs according to their potential to exert DDIs in TLR4-dependent manner.