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.
ABSTRACT
BACKGROUND AND PURPOSE: Cyclosporine A (CyA) is an immunosuppressant drug used to treat various autoimmune diseases and transplantations. It has been reported that, in humans, CyA is metabolized by cytochrome P450 (CYP) 3A or excreted by P-glycoprotein/multidrug resistant protein (MRP) 2. Pravastatin, a statin, is used to treat hyperlipidemia and has also been reported to be excreted primarily by MRP2. We observed an increased blood CyA level in a patient following pravastatin administration, suggesting the possibility that CyA interacted with the pravastatin via MRP2. The aim of the study reported here was to investigate the effects of pravastation on CyA transport via MRP2 using a human colon adenocarcinoma (Caco-2) monolayer model system. METHODS: Calcein, a substrate of MRP families, was first added to the tissue culture medium of the Caco-2 cells, and CyA (5, 50 microM) and pravastatin (0.1, 1.0 mM) were then added to the apical and basolateral sides. After a 30-min incubation, calcein was effluxed from the Caco-2 cells and the level in the culture medium was assayed. CyA was then added to the tissue culture medium of the Caco-2 cells, and pravastatin (0.1, 0.5, 1.0 mM) was added to the apical and basolateral sides. After a 30-min incubation, CyA was effluxed from the Caco-2 cells, and the level in the culture medium was assayed. RESULTS: The calcein efflux to the apical side was decreased significantly by the addition of pravastatin (1.0 mM) and CyA (5, 50 microM), respectively. The CyA efflux to the apical side was decreased significantly by the addition of pravastatin (1.0 mM). CONCLUSIONS: Based on these results, we suggest that CyA transport may be competitively inhibited by pravastatin via MRP2.
