Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

Abstract

Abstract. In irinotecan (CPT-11)-based chemotherapy, neutropenia and diarrhea are often induced. In the present study, the clinical significance of the concentration ratios of 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronide (SN-38G) and SN-38 in the plasma in predicting CPT-11-induced neutropenia was examined. A total of 17 patients with colorectal cancer and wild-type UDP-glucuronosyltransferase (UGT)1A1 gene were enrolled and treated with CPT-11 as part of the FOLFIRI regimen [CPT-11 and fluorouracil (5-FU)]. Blood was taken exactly 15 min following a 2-h continuous infusion of CPT-11. Plasma concentrations of SN-38, SN-38G and CPT-11 were determined by a modified high-performance liquid chromatography (HPLC) method. The median, maximum and minimum values of plasma SN-38G/SN-38 ratios were 4.25, 7.09 and 1.03, respectively, indicating that UGT activities are variable among patients with the wild-type UGT1A1 gene. The plasma SN-38G/SN-38 ratios decreased with an increase in the trial numbers of chemotherapy (r= 0.741, p= 0.000669), suggesting that CPT-11 treatment suppresses UGT activity, and the low plasma SN-38G/SN-38 ratios resulted in the induction of greater neutropenia. However, in this analysis, 2 clearly separated regression lines were observed between plasma SN-38G/SN-38 ratios and neutropenia induction. In conclusion, UGT activity involved in SN-38 metabolism is variable among patients with the wild-type UGT1A1 gene, and each CPT-11 treatment suppresses UGT activity. One-point determination of the plasma SN-38G/SN-38 ratio may provide indications for the prediction of CPT-11-induced neutropenia and adjustment of the optimal dose, although further studies are required.

Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai

“…About 2 ml of peripheral blood sample was taken 1.5 and 49 h after CPT-11 infusion for SN-38 plasma concentration detection by HPLC (Hirose et al 2012; Schoemaker et al 2003), and CPT-11 dosage was lowered by 20–25 % in case of Grade III° adverse effects.…”

“…Ethnic differences exist in UGT1A1 enzyme activity and gene polymorphisms (Kaniwa et al 2005), which are closely related to CPT-11 adverse effects (Innocenti et al 2004; Massacesi et al 2006) but they are uncertain with efficacy (Shulman et al 2011; Liu et al 2008). In addition, studies have found that AUC SN-38 or AUC SN-38G /AUC SN-38 is associated with neutropenia after CPT-11 treatment (Hirose et al 2012; Canal et al 1996), which indicate that CPT-11 or SN-38 pharmacokinetics is as important as UGT1A1 gene polymorphism analysis in predicting CPT-11-related adverse effects, even in dose individualization sets. Presently, data are limited about the role of UGT1A1*28 genotype and SN-38 pharmacokinetics in predicting CPT-11 efficacy and adverse effects, so our study reviewed the plasma SN-38 peak and valley concentration, treatment efficacy, and adverse effects in 98 cases with (TA) 6 /(TA) 6 and (TA) 6 /(TA) 7 genotypes who were treated with CPT-11 as first-line chemotherapy, in order to determine whether there is a relationship between plasma SN-38 peak and valley concentration and efficacy or adverse effects in patients with different genotypes, and provide theoretical basis for CPT-11 treatment individualization based on UGT1A1*28 genotype in combination with SN-38 pharmacokinetics analysis.…”

Correlation of UGT1A1 * 28 and * 6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients

“…CPT-11 is metabolized by carboxylesterase (CES) to form the active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin). This active metabolite is 100e1000-fold more cytotoxic than CPT-11 and interferes with tumor cell division by inhibiting the activity of topoisomerase I. SN-38 is then converted to a water-soluble inactive metabolite SN-38 glucuronide (SN-38G), by UDPglucuronosyltransferases (UGTs) [3,4].…”

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

“…A precipitating reagent reported by Hirose and colleagues that contained equal parts of methanol, ethylene glycol, and 1.0 mol/L zinc sulfate was used for extraction/precipitation of proteins (14). Prior to extraction, serum volume was extended by diluting with an equal part of water; water was also added to the tissues (10 parts water to 1 part tissue), which were then homogenized on ice using a Powergen-35 homogenizer equipped with a 7 Â 110 mm 2 tip for 2 minutes at 30,000 rpm (Fisher Scientific).…”