Effect of X-ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats.

Abstract

Concurrent chemoradiation with irinotecan hydrochloride (CPT-11) is accepted for cancer treatment. However, the effects of X-ray irradiation on chemotherapeutics in the plasma remain unclear. We evaluated the pharmacokinetics of CPT-11 in rats after exposure to X-ray irradiation and examined the changes of protein and mRNA expression of CES1 and CYP3A1. The X-ray irradiation with 1Gy and 5Gy was delivered to the whole body of rats. CPT-11 at 30 and 60mg/kg, respectively, was intravenously infused 24h after irradiation. CPT-11 was determined by RP-HPLC in plasma. ELISA and PCR were used to analyze the protein and mRNA expression of CES1 and CYP3A1, respectively. Compared with control rats, the X-ray irradiation decreased the AUC of CPT-11 (30mg/kg) by 15.6% at 1Gy and 39.0% at 5Gy and increased the CL by 60.0% at 5Gy. The X-ray irradiation could also decrease the AUC of CPT-11 (60mg/kg) and increase the CL. In addition, the protein and mRNA expression of CES1 and CYP3A1 were increased significantly in rats after irradiation. This study found significant changes in the pharmacokinetics of CPT-11 in rats after exposure to X-ray irradiation, and they might be due to significant increases in the expressions of CYP3A1 and CES1. The pharmacokinetics of CPT-11 should be rechecked, and the optimal CPT-11 dose should be reevaluated during concurrent chemoradiation therapy.