Pharmacokinetic Changes of Irinotecan by Intestinal Alkalinization in an Advanced Colorectal Cancer Patient

Abstract

The prevention of irinotecan (CPT-11)-induced diarrhea, a well-known adverse reaction to the drug, by treatment with intestinal alkalinization has been carried out in patients with colorectal cancer in Japan. Under acidic conditions, CPT-11 and its active metabolite, SN-38, exists preferably as the lactone form, whereas both exist as the carboxylate form under basic conditions. It has been suggested that the lactone forms of both CPT-11 and SN-38 are diffused passively across the intestinal mucosal membranes, whereas the carboxylate forms are actively transported. The intestinal uptake rate of both forms appears to be pH sensitive under physiological conditions, but it remains unclear whether intestinal alkalinization treatment affects the pharmacokinetics of CPT-11 and SN-38. This study was designed to evaluate the pharmacokinetics of CPT-11 and SN-38 in a colorectal cancer patient with or without alkalinization treatment. We found that intestinal alkalinization significantly decreased the plasma levels of CPT-11 and SN-38. In particular, the AUC of SN-38 was markedly decreased to 56 from 107 ng.h/mL. Intestinal alkalinization was effective in preventing CPT-11-induced diarrhea, but this treatment changed the pharmacokinetics of CPT-11 and SN-38 in the body.

Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case for Prophylaxis

“…Alkalization did not appear to decrease blood levels of CPT-11 or its active metabolites [85] and did not affect antitumor response rates [83]. However in a case report intestinal alkalization significantly decreased plasma levels of SN-38 and CPT-11 [86]. Also the prophylaxis is extremely cumbersome requiring daily consumption of highly alkalized water in excess of 2–3L/day for the entire course of therapy [83].…”

A randomised double-blind placebo-controlled phase II study of AGI004 for control of chemotherapy-induced diarrhoea

“…Moreover, any potential agent for CID prevention must be well tolerated with a low risk of drug interactions. Therefore, even though a possible role of intestinal alkalisation for CID prevention has been suggested, its usefulness is potentially limited by the changes it causes in the pharmacokinetics and plasma levels of irinotecan (Hamada et al , 2005). A further limiting factor for some preventative agents, despite evidence that they may have a beneficial effect on the incidence or severity of CID, is difficulty in administration, such as need for parenteral administration (Rosenoff et al , 2006; Li et al , 2009), or patient acceptability, particularly in the setting of other treatment toxicities such as nausea or mucositis, which may limit patient compliance with additional oral medication, or potential drug interactions with other medication (Michael et al , 2004).…”

“…Oral alkalisation of the gastrointestinal tract has also been reported to have a beneficial effect in preventing delayed diarrhoea in patients receiving irinotecan-containing chemotherapy (Takeda et al , 2001; Valenti Moreno et al , 2006), but again these studies have also been limited by small sample size and the possibility that this approach alters the pharmacokinetics of irinotecan in vivo (Hamada et al , 2005). …”

Biweekly Administration of Irinotecan (Cpt-11) Plus Cisplatin With an Antidiarrheal Program of Intestinal Alkalization to Reduce Diarrhea in Cancer Patients

“…Considering the reduction of absorption by intestinal epithelium of SN-38 and CPT-11, the intestinal alkalization may influence on enterohepatic circulation and their pharmacokinetics. Hamada et al reported a case report, in which intestinal alkalization decreased the plasma levels of CPT-11 and SN-38 25) . However, Tamura T et al compared the pharmacokinetics of CPT-11 with and without intestinal alkalization in a cross-over study using 10 colorectal cancer patients 26) .…”