The modulation of irinotecan-induced diarrhoea and pharmacokinetics by three different classes of pharmacologic agents

Diarrhoea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11) in the clinical setting. This study was designed to evaluate the effects of different pharmacological agents in the modulation of CPT-11 induced diarrhoea in Sprague-Dawley rats. We studied the effects of intravenous valproic acid (VPA), ceftriaxone (CTX) and oral charcoal in the modulation of CPT-11 induced diarrhoea. Male Sprague-Dawley rats (n=7 per group) were given CPT-11 60 mg/kg as intravenous injection from day 1 to 5 (total dose 300 mg/kg) in all treatment groups. Group 1 (G1) rats only received CPT-11, group 2 to 6 (G2 to G6) rats received in addition to IV CPT-11 60 mg/kg, IV valproic acid (VPA) 200 mg/kg (G2), IV VPA 200 mg/kg + IV ceftriaxone (CTX) 100 mg/kg (G3), IV VPA 200 mg/kg + oral activated charcoal 250 mg administered twice daily (G4), IV CTX 100 mg/kg (G5) and oral charcoal 250 mg every 12 hourly (G6). We compared the pharmacokinetics of total CPT-11 and its metabolites and the frequency and grade of diarrhoea in each group of rats. There were no significant differences in the pharmacokinetic parameters of total CPT-11 between treatment groups (p>0.05). Cotreatment with CTX and charcoal resulted in a lower total SN-38G AUC0-∞ (p<0.05 and p<0.01, respectively). Cotreatment with CTX also resulted in a lower Cmax for total SN-38G compared to other groups (p<0.01). A higher frequency of grade 3 diarrhoea was observed in G1 rats compared to other groups. Co-treatment with VPA (log OR: -1.13; 95% CI: -1.85, -0.41) or CTX (log OR: -1.66; 95% CI: -2.43, -0.88) were found to be associated with a lower odds of grade 3 diarrhoea compared to control or charcoal treated groups. Our findings indicate that CPT-11 treated rats given VPA and CTX, either alone or in combination has similar effects in preventing high grade diarrhoea. Activated charcoal was not found to be effective in the prevention of high grade diarrhoea.