Effect of intact oxaliplatin in plasma on a cold allodynia after multiple administrations in colorectal cancer model rats

Abstract

Oxaliplatin (L-OHP)-induced acute neuropathy is a major factor for influencing treatment compliance in patients receiving chemotherapy for colorectal cancer (CRC). Acute neuropathy is caused by the intact L-OHP affecting the function of transient receptor potential vanilloid 1 (TRPV1) channel. In this study, the effectiveness of the detection of the intact L-OHP and the association with the severity of L-OHP-induced acute neuropathy were investigated using a rat model of CRC. Wistar male rats were prepared as models of CRC by using 1,2-dimethylhydrazine (DMH) and dextran sulfate. Intravenous L-OHP was administered (weekly) to CRC rats for 4 weeks, at doses of 3, 5, or 8 mg/kg, respectively. Pharmacokinetic and tumor distribution profiles of animals with intact L-OHP were observed on days 1 and 22. Cold allodynia was determined as a read-out of acute neuropathy using the acetone test over the 4 weeks. The mean AUC0-∞ values for the intact L-OHP were increased dose-dependently at the three doses. The accumulation of intact L-OHP was confirmed following an increase in L-OHP concentration on day 22. Acute neuropathy was observed from day 2 at all doses and the withdrawal response correlated with AUC (R2 =0.9816). To prevent the onset of L-OHP-induced acute neuropathy, the timely detection of the intact L-OHP is important. These findings could be a basis of the establishment a pharmacokinetic and toxicodynamic model to aid the planning of therapy cycle completion for CRC.