Irinotecan is a chemotherapeutic drug used in the treatment of advanced colorectal cancer and elevated blood concentrations of its active metabolite, SN-38 leads to increased gastrointestinal (GI) toxicity and diarrhea in patients. In this study, we investigated the effects of inflammation on the pharmacokinetics (PK) of irinotecan (CPT-11) and its active metabolite, SN-38. Mice were i.p.-injected with either saline or lipopolysaccharide (LPS) to induce inflammation. After 16 h, irinotecan was administered orally. Blood was collected from the tail vein of mice from 0 to 24 h after dosing. Concentrations of irinotecan, SN-38 and SN-38G were analyzed using LC-MS/MS. The AUC, Cmax, and tmax were derived using WinNonlin® 5.2. A PK model was developed using Phoenix NLME® to describe the PK of irinotecan and SN-38 during inflammation. Results indicated a significant increase in the blood concentrations of irinotecan and SN-38 in mice during inflammation. The AUC of irinotecan and SN-38 in LPS group were 2.6 and 2-folds, respectively, of those in control saline-treated mice. The Cmax of irinotecan and SN-38 in LPS treated mice were 2.4 and 2.3-folds of those in saline-treated mice. The PK model was successfully developed and validated. The best-fit plots of individual PK analysis showed a good correlation between observed and predicted concentrations of irinotecan and SN-38. Together, this study reveals that SN-38 concentrations are elevated during inflammation, which may increase the GI toxicity and diarrhea in patients who receive irinotecan; and the developed PK model can quantitatively describe the PK of irinotecan and SN-38 during inflammation.

中文翻译：

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炎症对伊立替康药代动力学和最佳拟合PK模型发展的影响。

伊立替康是一种化学疗法药物，用于治疗晚期大肠癌和血液中活性代谢产物浓度升高，SN-38会导致患者胃肠道（GI）毒性和腹泻增加。在这项研究中，我们调查了炎症对伊立替康（CPT-11）及其活性代谢产物SN-38的药代动力学（PK）的影响。给小鼠腹腔注射盐水或脂多糖（LPS）以诱导炎症。16小时后，口服伊立替康。给药后0至24小时从小鼠的尾静脉收集血液。使用LC-MS / MS分析了伊立替康，SN-38和SN-38G的浓度。AUC，Cmax和tmax使用5.2导出。使用Phoenix NLPK开发了一个PK模型来描述伊立替康和SN-38在炎症过程中的PK。结果表明，炎症期间小鼠中伊立替康和SN-38的血药浓度显着增加。LPS组中伊立替康和SN-38的AUC分别是对照组生理盐水处理小鼠的AUC的2.6倍和2倍。伊立替康和SN-38在LPS处理的小鼠中的Cmax分别是生理盐水处理小鼠的Cmax的2.4倍和2.3倍。PK模型已成功开发和验证。个体PK分析的最佳拟合图显示，伊立替康和SN-38的浓度与预期值之间具有良好的相关性。总之，这项研究表明，在炎症过程中SN-38的浓度会升高，这可能会增加接受伊立替康的患者的胃肠道毒性和腹泻。建立的PK模型可以定量地描述伊立替康和SN-38在炎症过程中的PK。