Development of a physiologically based pharmacokinetic model to predict irinotecan disposition during inflammation.

Irinotecan, a first-line chemotherapy for gastrointestinal (GI) cancers has been causing fatal toxicities like bloody diarrhea and steatohepatitis for years. Irinotecan goes through multiple-step drug metabolism after injection and one of its intermediates 7-ethyl-10-hydroxy-camptothecin (SN-38) is responsible for irinotecan side effect. However, it is unclear what is the disposition kinetics of SN-38 in the organs subjected to toxicity. No studies ever quantified the effect of each enzyme or transporter on SN-38 distribution. In current study, we established a new physiologically based pharmacokinetic (PBPK) model to predict the disposition kinetics of irinotecan. The PBPK model was calibrated with in-house mouse pharmacokinetic data and evaluated with external datasets from the literature. We separated the contribution of each parameters in irinotecan pharmacokinetics by calculating the normalized sensitivity coefficient (NSC). The model gave robust prediction of SN-38 distribution in GI tract, the site of injury. We identified that bile excretion and UDP-glucuronosyltransferases (UGT) played more important roles than fecal excretion and renal clearance in SN-38 pharmacokinetics. Our NSC showed that the impact of enzyme and transporter on irinotecan and SN-38 pharmacokinetics evolved when time continued. Additionally, we mapped out the effect of inflammation on irinotecan metabolic pathways with PBPK modelling. We discovered that inflammation significantly increased the blood and liver exposure of irinotecan and SN-38 in the mice receiving bacterial endotoxin. Inflammation suppressed UGT, microbial metabolism but increased fecal excretion. The present PBPK model can serve as an efficacious and versatile tool to quantitively assess the risk of irinotecan toxicity.

Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management.

The epidermal growth factor receptor (EGFR) family is a class of receptor tyrosine kinase playing a central role in carcinogenesis and cancer progression. The members of this family, particularly EGFR and human epidermal growth factor receptor 2 (HER2), are the most extensively studied drug targets for malignancy. Today, numerous tyrosine kinase inhibitors targeting EGFR family have been developed to combat non-small-cell lung cancer and breast cancer. However, severe gastrointestinal (GI) toxicity leading to dose reduction and treatment discontinuation hampers the therapeutic outcome of EGFR inhibitors. Diarrhea is one of the most frequent GI side effects, especially when it comes to second-generation EGFR inhibitors. Enterocytes apoptosis and increased inflammation accompany with many oral EGFR inhibitors. Loperamide and budesonide are the first-line treatment to manage such adverse effects. However, current prophylaxis and management are all empirical interventions to relieve the symptom. They do not specifically target the toxicological mechanism of EGFR inhibitors. Hereby, those anti-diarrhea agents do not work well when used in cancer patients experiencing EGFR inhibitor-induced diarrhea. On the other hand, the toxicological mechanism of EGFR inhibitor-induced diarrhea is poorly understood. Thus, determining the mechanism behind such diarrhea is urgently in need for developing genuinely effective anti-diarrhea agents. This review aims to call attention to EGFR inhibitor-induced diarrhea, a highly occurring and devastating cancer drug toxicity.

Effects of inflammation on irinotecan pharmacokinetics and development of a best-fit PK model.

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.

Effect of xanthan/enzyme-modified guar gum mixtures on the stability of whey protein isolate stabilized fish oil-in-water emulsions.

The effect of xanthan gum (XG) and enzyme-modified guar (EMG) gum mixtures on the physicochemical properties and oxidative stability of 2wt% whey protein isolate (WPI) stabilized oil-in-water (O/W) emulsions containing 20%v/v fish oil was investigated. EMG was obtained by hydrolyzing native guar gum using α-galactosidase enzyme. At higher gum concentrations (0.2 and 0.3wt%), the viscosity of the emulsions containing XG/EMG gum mixtures was significantly higher (P<0.05) of all emulsions. Increasing concentrations (0-0.3wt%) of XG/EMG gum mixtures did not affect the droplet size of emulsions. Microstructure images revealed decreased flocculation at higher concentrations. Primary and secondary lipid oxidation measurements indicated a slower rate of oxidation in emulsions containing XG/EMG gum mixtures, compared to XG, guar (GG), and XG/GG gum mixtures. These results indicate that XG/EMG gum mixtures can be used in O/W emulsions to increase physical and oxidative stabilities of polyunsaturated fatty acids in foods.