Abstract
Paclitaxel, a broad-spectrum antitumor drug, is widely used as a cytotoxic drug, while sorafenib as a multi-kinase inhibitor is a classic targeted drug. A number of clinical trials have combined paclitaxel and sorafenib for cancer treatment, with the expectation of better therapeutic effects. However, the toxicity and side effects in the treatment are significantly increased. In this report, the organic anion transport polypeptide 1b2 (Oatp1b2) overexpression cell model and the Oatp1b2 knockout (KO) rat model were used to investigate the drug-drug interactions (DDI) between paclitaxel and sorafenib. In Oatp1b2-overexpressed cells, sorafenib inhibited the uptake of paclitaxel in a concentration-dependent manner. In wild-type (WT) rats, sorafenib increased the systemic exposure and slowed the elimination of paclitaxel, resulting in DDI. In Oatp1b2 KO rats, however, the DDI disappeared. Interestingly, paclitaxel did not alter the pharmacokinetic profiles of sorafenib. Further studies found that sorafenib was not the substrate of Oatp1b2 in rats. In general, the combination of paclitaxel and sorafenib caused Oatp1b2-mediated DDI in vitro and in vivo, because sorafenib inhibited Oatp1b2 activity and affected the pharmacokinetic properties of paclitaxel. This study may provide useful information for understanding the role of OATP1B in paclitaxel-sorafenib interaction.