卡培他滨
伊立替康
药理学
基于生理学的药代动力学模型
药代动力学
药物相互作用
药品
化学
结直肠癌
医学
肿瘤科
内科学
癌症
作者
Shuhei Sakai,Shinji Kobuchi,Yukako Ito,Toshiyuki Sakaeda
标识
DOI:10.1016/j.xphs.2021.12.021
摘要
Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug-drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug-drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m2) were administered to rats, and blood (250 μL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and Ki values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI.
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